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Zambrano-Vásquez OR, Cortés-Camacho F, Castañeda-Sánchez JI, Aréchaga-Ocampo E, Valle-Velázquez E, Cabrera-Angeles JC, Sánchez-Gloria JL, Sánchez-Muñoz F, Arellano-Buendia AS, Sánchez-Lozada LG, Osorio-Alonso H. Update in non-alcoholic fatty liver disease management: role of sodium-glucose cotransporter 2 inhibitors. Life Sci 2025; 372:123638. [PMID: 40246191 DOI: 10.1016/j.lfs.2025.123638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 03/28/2025] [Accepted: 04/09/2025] [Indexed: 04/19/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes without significant alcohol consumption. It is closely associated with sedentarism, hypercaloric diets, obesity, dyslipidemia, insulin resistance, type 2 diabetes mellitus, and genetic predisposition. NAFLD comprises a spectrum of liver disorders, from simple steatosis to non-alcoholic (NASH) and liver cirrhosis. The complex etiological mechanisms include oxidative stress, inflammation, apoptosis, and fibrosis; therefore, its management is challenging. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i), a class of antidiabetic drugs, have emerged as promising therapeutic agents due to their ability to improve key metabolic parameters, including obesity, dyslipidemia, insulin resistance, and hyperglycemia. This review explores the cellular mechanisms by which SGLT2i, either as monotherapy or combined with other treatments, modulate signaling pathways involved in lipid and carbohydrate metabolism. Additionally, we examine their effects on oxidative stress, inflammation, fibrosis, and apoptosis, which are critical drivers of NAFLD progression. This review is intended to summarize the multiple benefits of SGLT2 inhibitors and to educate healthcare providers on the therapeutic potential of these drugs in order to foster their incorporation into effective NAFLD management plans.
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Affiliation(s)
- Oscar R Zambrano-Vásquez
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Ciudad de México 04960, Mexico; Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Fernando Cortés-Camacho
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Ciudad de México 04960, Mexico; Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Jorge I Castañeda-Sánchez
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, México City 04960, Mexico
| | - Elena Aréchaga-Ocampo
- Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Unidad Cuajimalpa, México City 05348, Mexico
| | - Estefanía Valle-Velázquez
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Juan C Cabrera-Angeles
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México City, Mexico
| | - José L Sánchez-Gloria
- Department of Internal Medicine, Division of Nephrology, Rush University Medical Center, Chicago, IL 60612, USA
| | - Fausto Sánchez-Muñoz
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Abraham S Arellano-Buendia
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Laura G Sánchez-Lozada
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Horacio Osorio-Alonso
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico.
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Saha T, Mehrotra S, Gupta P, Kumar A. Exosomal miRNA combined with anti-inflammatory hyaluronic acid-based 3D bioprinted hepatic patch promotes metabolic reprogramming in NAFLD-mediated fibrosis. Biomaterials 2025; 318:123140. [PMID: 39892017 DOI: 10.1016/j.biomaterials.2025.123140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 01/03/2025] [Accepted: 01/23/2025] [Indexed: 02/03/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a complex metabolic disorder, where the underlying molecular mechanisms are mostly not well-understood and therefore, warrants the need for therapeutic interventions targeting several metabolic pathways as a unified response. Of late, promising outcomes have been observed with mesenchymal stem cell-derived exosomes. However, reduced bioavailability due to systemic delivery and the need for repeated fresh isolation hinders their feasibility for clinical applications. In this regard, an 'off-the-shelf' 3D bioprinted hyaluronic acid-based hepatic patch to deliver encapsulated exosomes alone/or with hepatocytes (as dual-therapy) is developed as a holistic approach for ameliorating the disease condition and promoting tissue regeneration. The bioprinted hepatic patch demonstrated sustained and localized release of exosomes (∼82 % in 21 days), and healthy liver tissue-like mechanical properties while being biocompatible and biodegradable. Assessment in NAFLD rat models displayed alleviation of the altered biochemical parameters such as fat deposition, deranged liver functions, disrupted lipid, glucose, and insulin metabolism along with a reduction in localized inflammation, and associated liver fibrosis. The study suggests that a synergistic effect between the miRNA population of released exosomes, cell therapy, and the bioprinted matrix materials is crucial in targeting multiple complex metabolic pathways associated with the severity of the disease.
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Affiliation(s)
- Triya Saha
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India
| | - Shreya Mehrotra
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India; Centre for Environmental Science and Engineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India.
| | - Purva Gupta
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India
| | - Ashok Kumar
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India; Centre for Environmental Science and Engineering, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India; The Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India; Centre for Nanosciences, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India; Centre of Excellence for Materials in Medicine, Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Kanpur, 208016, UP, India.
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Shi J, Ma Y, Yu N, Zhang Y, Cao Z, Guan L, Liu X, Chen Z, Jia G. Key toxic pathways of hepatotoxicity induced by titanium dioxide nanoparticles through multi-omics analysis. Food Chem Toxicol 2025; 201:115457. [PMID: 40250523 DOI: 10.1016/j.fct.2025.115457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 04/13/2025] [Accepted: 04/13/2025] [Indexed: 04/20/2025]
Abstract
The liver is considered a target organ for the accumulation and toxic effects of nanomaterials exposed to the body, especially after oral exposure, but the key toxic pathways have not been fully defined. This study focused on the hepatotoxicity of titanium dioxide nanoparticles (TiO2 NPs) in vivo and in vitro, and tried to identify key toxic pathways using the concept of systems biology and multi-omics methods. In vivo, protein and metabolomic sequencing were performed on the liver of SD rats (0, 50 mg/kg, 90 days), and 386 differential proteins and 29 differential metabolites were screened out, respectively, and the joint analysis found that they were significantly enriched in alanine, aspartate and glutamate metabolism, and butanoate metabolism. In vitro, exposure to TiO2 NPs could induce cytotoxicity and omics changes at different molecular levels in human hepatocellular carcinoma cells. Single omic analysis showed that differentially expressed proteins and metabolites were 80 and 222, respectively. The enriched pathways related to steroid biosynthesis, cholesterol metabolism at the combine levels of proteome and metabolome. KEGG enrichment analysis showed that PI3K-Akt signaling pathway and PPAR signaling pathway were both significantly affected in vitro and in vivo. Through multi-omics analysis, this work offered fresh perspectives and avenues for research on the toxicity mechanism of TiO2 NPs.
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Affiliation(s)
- Jiaqi Shi
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, 100191, People's Republic of China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University, Beijing, 100191, People's Republic of China
| | - Ying Ma
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, 100191, People's Republic of China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University, Beijing, 100191, People's Republic of China
| | - Nairui Yu
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, 100191, People's Republic of China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University, Beijing, 100191, People's Republic of China
| | - Yi Zhang
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, 100191, People's Republic of China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University, Beijing, 100191, People's Republic of China
| | - Zongfu Cao
- National Research Institute for Family Planning, Beijing, 100081, People's Republic of China; National Human Genetic Resources Center, Beijing, 102206, People's Republic of China
| | - Li Guan
- Department of Occupational Disease, Peking University Third Hospital, Beijing, 100191, People's Republic of China
| | - Xiaodong Liu
- Beijing Institute of Occupational Disease Prevention and Treatment, No. 50 Yikesong Xiangshan, Haidian District, Beijing, 100093, People's Republic of China
| | - Zhangjian Chen
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, 100191, People's Republic of China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University, Beijing, 100191, People's Republic of China.
| | - Guang Jia
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing, 100191, People's Republic of China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University, Beijing, 100191, People's Republic of China
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Zhang Y, Li J, Wang Z, Chen J, Zhao M, Guo C, Wang T, Li R, Zhang H, Ma X, Wen Y, Zeng J, Efferth T. Preclinical evidence construction for epigallocatechin-3-gallate against non-alcoholic fatty liver disease: a meta-analysis and machine learning study. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156651. [PMID: 40327947 DOI: 10.1016/j.phymed.2025.156651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 10/20/2024] [Accepted: 03/14/2025] [Indexed: 05/08/2025]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant health concern worldwide, exhibiting an increasing incidence that necessitates immediate intervention. Epigallocatechin-3-gallate (EGCG) has shown significant pharmacological benefits for liver diseases, including NAFLD. However, its efficacy in this context has not been systematically evaluated. PURPOSE This meta-analysis aimed to consolidate preclinical evidence on the effectiveness and mechanisms of EGCG in treating NAFLD. METHODS We conducted a comprehensive literature search for preclinical studies from the inception of each database to April 2024, including Excerpta Medica Database, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang, and China Science and Technology Journal Database. These studies were manually screened based on predefined criteria. Data extraction was followed by pooled effect size calculations using Stata 16.0. A machine learning approach was also utilized to examine the temporal relationships among variables. RESULTS Seventeen studies, involving 293 animals, were analyzed. Our analysis indicates that EGCG significantly reduces ALT, AST, hepatic triglyceride, serum TG, hepatic TC, serum TC. The targets of EGCG may include antioxidants, regulation of lipid metabolism, anti-inflammation, improvement of insulin resistance, and inhibition of hepatic fibrosis. EGCG exerted its effects on NAFLD by modulating key signaling pathways, including PI3K/Akt/AMPK, TGF-β/Smad, Nrf2, NF-κB, and ROS/MAPK, highlighting its multifaceted mechanisms of action. The machine learning methods employed to ascertain the temporal relationship between the intervention and the outcome indicated that the optimal duration of the intervention was 10 to 15 weeks. CONCLUSIONS The efficacy of EGCG in treating NAFLD has been predicted within a time frame of 10-15 weeks. It may exert its effects primarily through the NF-κB and Nrf2 pathways, which regulate the ROS phenotype. EGCG may represent a promising target for the treatment of NAFLD.
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Affiliation(s)
- Yuanhao Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China; School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Jianguo Li
- Bazhong Hospital of Traditional Chinese Medicine, Bazhong, China
| | - Zexin Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jie Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China; School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Maoyuan Zhao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Cui Guo
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Tingyao Wang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Ruilin Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Hebin Zhang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Xiao Ma
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Yueqiang Wen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Jinhao Zeng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China; School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
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Yang R, Jiang Q, Liu W, Wang F, Cao S. Serum polychlorinated biphenyls as a risk factor for MASLD: Exploring the association and underlying mechanisms. THE SCIENCE OF THE TOTAL ENVIRONMENT 2025; 981:179617. [PMID: 40354702 DOI: 10.1016/j.scitotenv.2025.179617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 04/30/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Fatty liver disease, a growing global health issue, is closely tied to metabolic disorders. The 2023 definition of metabolic-associated steatotic liver disease (MASLD) incorporates cardiometabolic risk factors, but the potential role of persistent organic pollutants (POPs) like polychlorinated biphenyls (PCBs), remains underexplored. Investigating the impact of environmental toxins on liver health is crucial for understanding emerging public health risks. METHODS 1080 participants were included from the 1999-2018 National Health and Nutrition Examination Survey (NHANES). We employed weighted generalized linear models, weighted quantile sum regression, and Bayesian kernel machine regression to assess the relationship between serum PCB levels and MASLD, with NAFLD included for comparison. Protein interaction and enrichment analyses were also conducted to explore the underlying mechanisms. RESULTS PCB146, PCB156, PCB187, PCB174, and PCB180 were significantly associated with an increased MASLD risk in the GLM. Significant positive associations were found between serum PCB mixtures and MASLD in the WQS model (β: 0.411, p: 0.0056) and BKMR model (p < 0.05), with PCB180 contributing the most (β: 0.644, PIP: 0.903). NAFLD did not show significant associations. Network pharmacological analysis demonstrated enrichment in the regulation of lipolysis of adipocytes and the cAMP signaling pathway, and PPAR-γ and MAOA show significant importance in the protein-protein interaction networks. CONCLUSION This study underscores the epidemiological and mechanical link between MASLD and PCB exposure, highlighting the superiority of MASLD in identifying the impact of POPs on liver disease risk and particularly identifying PCB180 as a sentinel marker for PCB surveillance.
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Affiliation(s)
- Ruichen Yang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Qingqing Jiang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Wentao Liu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Furong Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Shiyi Cao
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
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Matboli M, Saad M, Ahmed MF, Helmy Hasanin A, Ellithy GM, Abdelwahab MS, Eltantawy EHB, Hamam GG, Hamoud AE, El-Shafei MM, Samir N. Febuxostat alleviate metabolic dysfunction-associated steatohepatitis in rat model via targeting inflammation, cell death, and intestinal barrier dysfunction. Biomed Pharmacother 2025; 187:118086. [PMID: 40306176 DOI: 10.1016/j.biopha.2025.118086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/15/2025] [Accepted: 04/23/2025] [Indexed: 05/02/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) constitutes a global health threat with its ability to develop into liver cirrhosis and hepatocellular carcinoma (HCC). Emerging data suggests that oxidative stress and regulated cell death are major driving forces for liver inflammation in MASH. Febuxostat (Feb.), one of the Xanthine oxidase (XO) inhibitors, has shown promise in significantly improving the prognosis of MASH by reducing inflammatory cytokines and cell death. However, the underlying molecular mechanisms remain unclear. In this study, we evaluated the therapeutic effects of febuxostat on MASH through the modulation of cell death, inflammation, and intestinal permeability, focusing on hepatic mRNAs (HGS, SNF8, TSG101) and their epigenetic regulators (rno-miR-6216, rno-miR-1224). MASH was induced in Wistar rats via a High-sucrose high-fat (HSHF) diet over 14 weeks, followed by febuxostat treatment at doses of 1.5, 3, and 6 mg/kg/day for 4 weeks. Febuxostat treatment significantly improved liver function and lipid profiles, reduced hepatic steatosis, intralobular inflammation, and ballooning, and restored normal expression of the hepatic RNA panel by downregulating HGS, SNF8, and TSG101 mRNAs and their epigenetic regulators. Furthermore, febuxostat decreased serum levels of inflammatory (IL6), fibrosis (TGFB1), and cell death (TSG101) markers while reducing apoptosis and regulated cell death via modulation of Caspase-3 and LC3B expression. Improvements in intestinal permeability were evident via reductions in serum haptoglobin (Hpt) and TMAO and restoration of occludin expression. These findings highlight febuxostat as a promising therapeutic candidate for MASH by targeting key molecular mechanisms of liver inflammation and gut-liver axis dysfunction.
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Affiliation(s)
- Marwa Matboli
- Medical biochemistry and molecular biology department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Maha Saad
- Basic medical sciences department, Faculty of Medicine, Modern University for Technology and Information, Egypt
| | - Manar Fouad Ahmed
- Medical biochemistry and molecular biology department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Amany Helmy Hasanin
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ghada M Ellithy
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | | | - Ghada Galal Hamam
- Department of Histology, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
| | - Amany E Hamoud
- Anatomy and Embryology Department, Faculty of Medicine, Cairo University, Egypt
| | - Marwa M El-Shafei
- Pathology Department, Faculty of Oral and Dental Medicine, Misr International University, Obour, Qalyubiyya Governorate, Egypt
| | - Nehal Samir
- Medical biochemistry and molecular biology department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Taheri E, Yilmaz Y, Ghorat F, Moslem A, Zali MR. Association of diet quality scores with risk of metabolic-associated fatty liver disease in Iranian population: a nested case-control study. J Diabetes Metab Disord 2025; 24:46. [PMID: 39816985 PMCID: PMC11729581 DOI: 10.1007/s40200-024-01544-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 12/05/2024] [Indexed: 01/18/2025]
Abstract
Background and aim A healthy diet has been recommended for non-alcoholic fatty liver disease (NAFLD). We aim to investigate the associations of diet quality indices with the risk of developingmetabolic-associated fatty liver disease (MAFLD). Methods We conducted this nested case-control study by recruiting 968 cases with MAFLD and 964 controls from the participants of the baseline phase of the Sabzevar Persian Cohort Study (SPCS). MAFLD was defined as having a fatty liver index ≥ 60 plus at least one of the following: overweight or obese, Type II diabetes mellitus, or evidence of metabolic dysregulation. Healthy Eating Index-2015 (HEI-2015) and Alternative Healthy Eating Index-2010 (AHEI-2010) were calculated from a validated food frequency questionnaire. We estimated the associations of HEI-2015 and AHEI-2010 with MAFLD risk using multivariable logistic regression. Results Among those in the highest relative to the lowest quintile of HEI-2015 and AHEI-2010, the multivariable-adjusted odds ratios (OR) were 0.45 (95% CI [confidence interval] 0.29-0.69; P trend = 0.002) and 0.55 (95% CI 0.35-0.85; P trend = 0.04), respectively. Conclusion The results of our study suggest that there is a significant associationbetween adherence to a healthy diet, indicated by a higher score of HEI or AHEI, and a reduced likelihood of developingMAFLD. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-024-01544-x.
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Affiliation(s)
- Ehsaneh Taheri
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Türkiye
| | - Fereshteh Ghorat
- Non-communicable Diseases Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Alireza Moslem
- Department of Anesthesiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Disease Research Center, Research Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Wu Y, Dong P, Wu Q, Zhang Y, Xu G, Pan C, Tong H. Insights into Clinical Trials for Drugs Targeting MASLD: Progress, Challenges, and Future Directions. Clin Pharmacol Ther 2025; 117:1614-1626. [PMID: 39953659 DOI: 10.1002/cpt.3606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/29/2025] [Indexed: 02/17/2025]
Abstract
The transition in terminology from fatty liver disease to metabolic dysfunction-associated steatotic liver disease (MASLD) marks a considerable evolution in diagnostic standards. This new definition focuses on liver fat accumulation in the context of overweight/obesity, type 2 diabetes, or metabolic dysfunction, without requiring the exclusion of other concurrent liver diseases. The new definition also provides clear guidelines for defining alcohol consumption in relation to the disease. MASLD is currently acknowledged as the most widespread liver disorder globally, affecting ~25% of the population. Despite the extensive array of clinical trials conducted in recent years, the number of approved treatments for metabolic dysfunction-associated fatty liver disease is very limited. In the review critically evaluates the results of clinical trials of related drugs and assesses the future directions for drug development trials. The renaming of MASLD presents new challenges and opportunities for the design of clinical trials and the selection of target populations for drug development.
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Affiliation(s)
- Yu Wu
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Pu Dong
- Department of Infectious Diseases, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qifang Wu
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Ya Zhang
- Hepatology Diagnosis and Treatment Center & Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chenwei Pan
- Department of Infectious Diseases, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Precision General Practice and Health Management, Wenzhou, China
| | - Haibin Tong
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
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Jamialahmadi T, Looha MA, Jangjoo S, Emami N, Abdalla MA, Ganjali M, Salehabadi S, Karav S, Sathyapalan T, Eid AH, Jangjoo A, Sahebkar A. Predictive performance of noninvasive factors for liver fibrosis in severe obesity: a screening based on machine learning models. J Diabetes Metab Disord 2025; 24:54. [PMID: 39834350 PMCID: PMC11741961 DOI: 10.1007/s40200-025-01564-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 01/05/2025] [Indexed: 01/22/2025]
Abstract
Objectives Liver fibrosis resulting from nonalcoholic fatty liver disease (NAFLD) and metabolic disorders is highly prevalent in patients with severe obesity and poses a significant health challenge. However, there is a lack of data on the effectiveness of noninvasive factors in predicting liver fibrosis. Therefore, this study aimed to assess the relationship between these factors and liver fibrosis through a machine learning approach. Methods This study involved 512 patients who underwent bariatric surgery at an outpatient clinic in Mashhad, Iran, between December 2015 and September 2021. Patients were divided into fibrosis and non-fibrosis groups and demographic, clinical, and laboratory variables were applied to develop four machine learning models: Naive Bayes (NB), logistic regression (LR), Neural Network (NN) and Support Vector Machine (SVM). Results Among the 28 variables considered, six variables including (fasting blood sugar (FBS), skeletal muscle mass (SMM), hemoglobin, alanine transaminase (ALT), aspartate transaminase (AST) and triglycerides) showed high area under the curve (AUC) values for the diagnosis of liver fibrosis using 2D shear wave elastography (SWE) with LR (0.73, 95% CI: 0.65, 0.81) and SVM (0.72, 59% CI: 0.64, 0.80) models. Furthermore, the highest sensitivities were reported with SVM (0.83, 95% CI: 0.72, 0.91) and NB (0.66, 95% CI: 0.53, 0.77) models, respectively. Conclusion The predictive performance of six noninvasive factors of liver fibrosis was significantly superior to other factors, showing high application and accuracy in the diagnosis and prognosis of liver fibrosis. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-025-01564-1.
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Affiliation(s)
- Tannaz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Azizmohammad Looha
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Jangjoo
- School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Emami
- School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammed Altigani Abdalla
- Allam Diabetes Centre, Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School (HYMS), University of Hull, Hull, UK
| | - Mohammadreza Ganjali
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sepideh Salehabadi
- School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sercan Karav
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale, 17100 Turkey
| | - Thozhukat Sathyapalan
- Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | - Ali H. Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Ali Jangjoo
- Surgical Oncology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Institute of Medical and Technical Sciences, Saveetha Medical College and Hospitals, Saveetha University, Chennai, India
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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10
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Xiao L, Zeng L, Wang J, Hong C, Zhang Z, Wu C, Cui H, Li Y, Li R, Liang S, Deng Q, Li W, Zou X, Ma P, Liu L. Development and Validation of Machine Learning-Based Marker for Early Detection and Prognosis Stratification of Nonalcoholic Fatty Liver Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e10527. [PMID: 40432473 DOI: 10.1002/advs.202410527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 04/27/2025] [Indexed: 05/29/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and is considered the hepatic manifestation of metabolic syndrome, triggering out adverse outcomes. A stacked multimodal machine learning model is constructed and validated for early identification and prognosis stratification of NAFLD by integrating genetic and clinical data sourced from 36 490 UK Biobank and 9 007 Nanfang Hospital participants and extracted its probabilities as in-silico scores for NAFLD (ISNLD). The efficacy of ISNLD is evaluated for the early prediction of severe liver disease (SeLD) and analyzed its association with metabolism-related outcomes. The multimodal model performs satisfactorily in classifying individuals into low- and high-risk groups for NAFLD, achieving area under curves (AUCs) of 0.843, 0.840, and 0.872 within training, internal, and external test sets, respectively. Among high-risk group, ISNLD is significantly associated with intrahepatic and metabolism-related complications after lifestyle factors adjustment. Further, ISNLD demonstrates notable capability for early prediction of SeLD and further stratifies high-risk subjects into three risk subgroups of elevated risk for adverse outcomes. The findings emphasize the model's ability to integrate multimodal features to generate ISNLD, enabling early detection and prognostic prediction of NAFLD. This facilitates personalized stratification for NAFLD and metabolism-related outcomes based on digital non-invasive markers, enabling preventive interventions.
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Affiliation(s)
- Lushan Xiao
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Lin Zeng
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, 518133, China
| | - Jiaren Wang
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Chang Hong
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ziyong Zhang
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Chengkai Wu
- School of Public Health, Southern Medical University, Guangzhou, 510515, China
- School of Health Management, Southern Medical University, Guangzhou, 510515, China
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Hao Cui
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yan Li
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ruining Li
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Shengxing Liang
- School of Public Health, Southern Medical University, Guangzhou, 510515, China
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Qijie Deng
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Wenyuan Li
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xuejing Zou
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Pengcheng Ma
- School of Public Health, Southern Medical University, Guangzhou, 510515, China
- School of Health Management, Southern Medical University, Guangzhou, 510515, China
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Li Liu
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
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11
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Guo Z, Yang S, Qi L, Ma X, Wang Y, Li B, He J. Lactobacillus acidophilus KLDS1.0901 ameliorates non-alcoholic fatty liver disease by modulating the tryptophan metabolite indole-3-aldehyde and acting on its receptor AhR. Food Funct 2025. [PMID: 40423690 DOI: 10.1039/d4fo05280c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2025]
Abstract
Our previous study demonstrated that Lactobacillus acidophilus KLDS1.0901 significantly alleviated symptoms of high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and showed a strong association with the gut microbiota; however, the underlying mechanisms remained unclear. In this study, we focused on changes in intestinal metabolic pathways in mice following intervention with Lactobacillus acidophilus KLDS1.0901, using non-targeted metabolomics. Tryptophan metabolism was found to be closely associated with NAFLD alleviation, and indole-3-aldehyde (IAld) was identified as a key target. Animal experiments showed no significant differences in the levels of liver triglycerides, fasting blood glucose, alanine aminotransferase, aspartate aminotransferase, IL-6, IL-1β, TNF-α, and IL-10 between the direct-feeding IAld group and the Lactobacillus acidophilus KLDS1.0901 group. This suggests that the IAId, produced by Lactobacillus acidophilus KLDS1.0901, is the key intermediate mediator responsible for its improvement of NAFLD. The alleviating effect of Lactobacillus acidophilus KLDS1.0901 on NAFLD symptoms was suppressed after the inhibition of the IAld receptor aromatic hydrocarbon receptor (AhR), suggesting that the bacterium relies on the AhR signaling pathway to mediate its effect on NAFLD. Cellular experiments showed that IAld significantly reduced triglyceride content, decreased lipid accumulation, and increased glycogen levels in oleic acid-induced cells. The effects of IAld on gene transcription levels in oleic acid-induced HepG2 cells were further analyzed using high-throughput sequencing. Transcriptomic analysis revealed that IAld regulates key pathways, including the NF-κB, chemokine and AGE-RAGE signaling pathways. Our study identified the ameliorative effects of tryptophan metabolites, particularly IAld, on NAFLD, along with the underlying mechanisms, offering new insights into potential treatment strategies for NAFLD.
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Affiliation(s)
- Zhengtao Guo
- Food College, Northeast Agricultural University, Harbin 150030, China.
- Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin 150030, China
| | - Shengjun Yang
- Food College, Northeast Agricultural University, Harbin 150030, China.
- Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin 150030, China
| | - Liwen Qi
- Food College, Northeast Agricultural University, Harbin 150030, China.
- Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin 150030, China
| | - Xinming Ma
- Food College, Northeast Agricultural University, Harbin 150030, China.
- Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin 150030, China
| | - Yanbo Wang
- Food College, Northeast Agricultural University, Harbin 150030, China.
- Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin 150030, China
| | - Bailiang Li
- Food College, Northeast Agricultural University, Harbin 150030, China.
- Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin 150030, China
| | - Jian He
- National Center of Technology Innovation for Dairy, Hohhot 010110, China.
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12
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Yang B, Yang T, Hou C, Li Y, Wang Q. Patients with chronic hepatitis B exhibiting significant inflammation and fibrosis should pay particular attention to the status of hepatic steatosis during antiviral therapy. Virol J 2025; 22:164. [PMID: 40420107 DOI: 10.1186/s12985-025-02703-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 03/11/2025] [Indexed: 05/28/2025] Open
Abstract
OBJECTIVE This study aims to explore the effects of various hepatic steatosis conditions on histological outcomes in patients with significant inflammation and fibrosis in chronic hepatitis B (CHB) and analyze their impact on HBV virological suppression outcomes and biochemical improvement. METHOD This retrospective study included 219 chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogues therapy. Each of these patients underwent two liver biopsies. Patients were categorized into four groups based on hepatic steatosis status: sustained non-hepatic steatosis (n = 118), new-onset hepatic steatosis (n = 33), sustained hepatic steatosis (n = 37), and disappeared hepatic steatosis (n = 31). We compared the liver biochemical parameters and histological changes before and after treatment. Logistic regression analysis was performed to evaluate characteristics associated with the improvement of significant liver inflammation (G ≥ 2), significant fibrosis (S ≥ 2), and the persistence of hepatic steatosis. RESULTS After treatment, the sustained non-steatosis group exhibited the highest rate of improvement in baseline significant inflammation (75.31%), while the sustained steatosis group had the lowest (42.31%, p = 0.008). The sustained steatosis group also had the highest rate of inflammation progression (15.38%, p = 0.020) and was identified as a risk factor for inadequate baseline inflammation improvement (p = 0.006, OR = 0.244, 95% CI 0.090-0.665). In terms of baseline significant liver fibrosis improvement, the sustained non-hepatic steatosis group showed the highest improvement rate (67.14%), while the sustained hepatic steatosis group had the lowest (28.00%, p = 0.006). The new-onset steatosis group had the highest rate of liver fibrosis progression (15.00%, p = 0.027), and sustained hepatic steatosis was a risk factor for poor baseline fibrosis improvement (p = 0.001, OR = 0.180, 95% CI 0.064-0.507). Furthermore, the sustained hepatic steatosis group showed the smallest decrease in liver enzyme markers ALT, GGT, and ALP post-treatment, with reductions of 22.11% (p = 0.023), 13.86% (p = 0.003), and 1.98% (p = 0.025), respectively. Logistic regression analysis revealed that high baseline BMI and LDL-C levels were significantly associated with persistent fatty liver, with high BMI (p = 0.042, OR = 1.109, 95% CI 1.004-1.226) and high LDL-C (p < 0.001, OR = 2.570, 95% CI 1.524-4.332). CONCLUSION In CHB patients with significant inflammation and fibrosis, the persistence of hepatic steatosis during antiviral treatment may impede the improvement of inflammation and fibrosis, leading to disease progression and biochemical abnormalities.
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Affiliation(s)
- Bingqing Yang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Tianyuan Yang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Chenxue Hou
- Laboratory Department, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yue Li
- Laboratory Department, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
| | - Qi Wang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
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Wang J, He W, Cai X, Hu Z, Peng Y, Chen X, Yang P, Zeng X, Chen S, Wang D. Relative fat mass and risk of metabolic dysfunction associated steatotic liver disease and severe hepatic steatosis in U.S. adults: analysis of NHANES 2017-2020 data. BMC Gastroenterol 2025; 25:410. [PMID: 40426055 PMCID: PMC12117908 DOI: 10.1186/s12876-025-04006-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Accepted: 05/19/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Relative fat mass (RFM) is a novel, easily calculated, and cost-effective index of fat content and distribution in the body, associated with the odds of developing various obesity-related diseases. However, its association with metabolic dysfunction associated steatotic liver disease (MASLD) and severe hepatic steatosis (SHS) is underexplored. This study aims to examine the relationship between RFM and the odds of having MASLD or SHS in the general adult population. METHODS This was a population-based cross-sectional study using data from the National Health and Nutrition Examination Survey (2017.01-2020.03). The aim of the statistical analysis was to examine the association between RFM and the prevalence of MASLD and SHS. Logistic regression was applied to explore this relationship. Nonlinear associations between RFM levels and MASLD or SHS prevalence were assessed using smoothed curve fitting and threshold effect models. Subgroup analyses were conducted to evaluate the consistency of this association across different population groups. RESULTS A total of 6699 participants were included in this study, of whom 2825 had MASLD and 1834 had SHS. After adjusting for confounders, significant positive associations were observed between RFM and the prevalence of MASLD and SHS (odds ratio [OR]: 1.22, 95% confidence interval [CI: ] 1.18-1.26 and OR: 1.26, 95% CI: 1.21-1.30). Smoothed curve fitting and threshold effect analysis showed a nonlinear relationship between RFM and the prevalence of MASLD and SHS, with thresholds of 41.96 for MASLD prevalence and 40.42 for SHS prevalence. When the subgroups were analyzed according to sex, age, race, education level, smoking status, household income, body mass index, hypertension, and diabetes, no significant interactions were found between RFM and most subgroups. CONCLUSIONS Our results demonstrated a positive nonlinear relationship between RFM and the prevalence of MASLD and SHS, with a threshold effect. Lower RFM levels are associated with lower odds of MASLD and SHS. These findings suggest that RFM may serve as a simple, cost-effective tool for identifying individuals at increased odds of NAFLD and SHS in the general population.
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Affiliation(s)
- Jianjun Wang
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
- NHC Key Laboratory of Nuclear Technology Medical Transformation, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Wei He
- Department of Stomatology, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Xianfu Cai
- Department of Urology, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Zhaohui Hu
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Yonghai Peng
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Xi Chen
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Pei Yang
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Xintao Zeng
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
| | - Sirui Chen
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
| | - Decai Wang
- NHC Key Laboratory of Nuclear Technology Medical Transformation, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
- Department of Urology, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
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Thomas A, Thomas A. Managing Nonalcoholic Fatty Liver Disease Through Structured Lifestyle Modification Interventions. Am J Lifestyle Med 2025:15598276251346717. [PMID: 40438150 PMCID: PMC12106371 DOI: 10.1177/15598276251346717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 05/14/2025] [Accepted: 05/16/2025] [Indexed: 06/01/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a significant global health burden. It comprises a broad pathological spectrum ranging from simple liver steatosis to steatohepatitis with variable degrees of fibrosis, and liver failure. Patients with NAFLD have an increased risk of liver-related and overall mortality. While the trials to assess the efficacy of the medications are ongoing, lifestyle modification is the first line of therapy recommended. The primary aim of this review paper is to synthesize literature related to current evidence-based lifestyle interventions for preventing and managing NAFLD. The review and synthesis of the literature reveal that personalized nutritional, exercise, and behavior change interventions are effective in managing NAFLD. Evidence suggests that there are several gaps in managing NAFLD. The gaps discussed in this paper include a lack of awareness of the disease, ineffective patient-provider communication, shortage of specialists, under-recognition of the disease, and liver health disparities. This paper highlights the evidence-based opportunities to overcome those gaps, such as utilizing comprehensive models of care, clinical care pathways, and clinical practice guidelines. Primary care physicians and endocrinologists, who are the first point of contact must utilize these opportunities for diagnosing and managing patients with NAFLD.
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Affiliation(s)
- Andrew Thomas
- Internal Medicine, Southern Illinois Healthcare, Carbondale, IL, USA (AT)
| | - Annie Thomas
- Marcella Niehoff School of Nursing, Loyola University Chicago, Maywood, IL, USA (AT)
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15
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Salmanizadeh F, Sabzevari S, Shafieipour S, Zahedi MJ, Sarafinejad A. Challenges and needs in the management of non-alcoholic fatty liver disease from the perspective of gastroenterology and hepatology specialists: a qualitative study. BMC Gastroenterol 2025; 25:396. [PMID: 40405078 PMCID: PMC12096504 DOI: 10.1186/s12876-025-03921-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 04/21/2025] [Indexed: 05/24/2025] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and it poses a significant threat to public health. There is insufficient documented evidence about the problems and needs of patients and physicians in managing NAFLD. This study aimed to explore the challenges and needs in managing NAFLD from the perspective of gastroenterology and hepatology (GH) specialists. METHODS This qualitative study was conducted from January to September 2023. Fifteen Iranian GH specialists selected by purposive sampling. Data were collected through semi-structured interviews. The interviews were analyzed inductively using the Elo and Kyngas content analysis approach. The criteria proposed by Guba and Lincoln were used to ensure the study's validity. RESULTS The identified challenges were divided into thirteen main categories (34 subcategories and 117 primary codes), and the identified needs were divided into eight main categories (21 subcategories and 97 primary codes). The main categories of the challenges were chronic nature and time-consuming differential diagnosis, complex treatment process, defects in the patient management process, shortcomings of the healthcare system, the effect of unhealthy eating and cultural and social factors on the diet, incorrect attitude of patients, lack of knowledge and awareness of patients, lack of comprehensive treatment plans based on patients' conditions, defect in knowledge and awareness of physicians, inadequate cooperation of patients, defects in the process of recording and monitoring information and providing feedback, insufficient policies and plans in the prevention of NAFLD, and economic problems. The main categories of needs included developing a comprehensive treatment plan, updating physicians' knowledge and creating standard treatment protocols, changing attitudes and empowering patients, informing and educating patients, establishing multi-specialty clinics for NAFLD treatment, establishing peer support groups and facilitating communication, utilizing digital technology to track patient information and monitor their progress, and supportive, educational, prevention, and management policies in the treatment of NAFLD. CONCLUSIONS This study showed that managing NAFLD involves physical, psychological, nutritional, sports, economic, and social aspects and requires multidisciplinary clinical approaches, digital technologies, and supportive and educational policies. These findings have important implications that can help patients, physicians, and policymakers design better lifestyle prescriptions to manage NAFLD.
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Affiliation(s)
- Farzad Salmanizadeh
- Student Research Committee, Faculty of Management and Medical Information Science, Kerman University of Medical Sciences, Kerman, Iran
| | - Sakineh Sabzevari
- Nursing Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Sara Shafieipour
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Science, Kerman University of medical Science, Kerman, Iran
| | - Mohammad Javad Zahedi
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Science, Kerman University of medical Science, Kerman, Iran
| | - Afshin Sarafinejad
- Clinical Informatics Research and Development Lab, Clinical Research Development Unit, Shafa Hospital, Kerman University of Medical Sciences, Kerman, Iran.
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16
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Cao B, Zhou J, Xia B, Li X, Wang R, Xu Y, Li C. Therapeutic potential of a choline-zinc-vitamin E nutraceutical complex in ameliorating thioacetamide-induced nonalcoholic fatty liver pathology in zebrafish. PLoS One 2025; 20:e0324164. [PMID: 40392901 PMCID: PMC12091810 DOI: 10.1371/journal.pone.0324164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 04/21/2025] [Indexed: 05/22/2025] Open
Abstract
Choline has been proven to be effective in maintaining liver function. However, the effect of choline, in combination with other nutrients, on the improvement of non-alcoholic fatty liver disease (NAFLD) remains unclear. This study aimed to investigate the potential effect of the nutraceutical complex containing choline bitartrate, zinc citrate, and dl-α-Tocopheryl acetate on NAFLD in the zebrafish model. The NAFLD model was induced in zebrafish by administering thioacetamide. Experimental groups were established, including a normal control group, the model control group, the positive control group, the nutraceutical complex intervention group, and the choline bitartrate alone intervention group. The intervention was administered to the zebrafish in a water-soluble form, while the positive control group received polyene phosphatidylcholine at a concentration of 50.0 μg/mL. Notably, the protective effect of the nutraceutical complex against NAFLD is more pronounced than that observed with choline bitartrate supplementation alone. The results of transcriptomics and quantitative real-time PCR showed that the potential mechanisms underlying the effects of the nutraceutical complex might involve the upregulation of acacia, acsl1a, fbp2 gene expression, and the downregulation of tbc1d1 gene expression. These results were further validated by western blotting and overexpression experiments. Our findings indicated that choline bitartrate, zinc citrate, and dl-α-Tocopheryl acetate can help improve NAFLD. The results of this study provide evidence for the application of the nutraceutical complex in the improvement of NAFLD.
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Affiliation(s)
- Bingbing Cao
- Hunter Biotechnology, Inc., Hangzhou, Zhejiang, The People’s Republic of China
| | - Jiali Zhou
- Hunter Biotechnology, Inc., Hangzhou, Zhejiang, The People’s Republic of China
| | - Bo Xia
- Hunter Biotechnology, Inc., Hangzhou, Zhejiang, The People’s Republic of China
| | - Xiaoqing Li
- Opella, Shanghai, The People’s Republic of China
| | - Rui Wang
- Opella, Shanghai, The People’s Republic of China
| | - Yiqiao Xu
- Hunter Biotechnology, Inc., Hangzhou, Zhejiang, The People’s Republic of China
| | - Chunqi Li
- Hunter Biotechnology, Inc., Hangzhou, Zhejiang, The People’s Republic of China
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Bahadoran Z, Azizi F, Ghasemi A. The association between serum and urinary nitric oxide metabolites and fatty liver index: a population-based study. Nitric Oxide 2025:S1089-8603(25)00044-8. [PMID: 40404044 DOI: 10.1016/j.niox.2025.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 05/18/2025] [Accepted: 05/18/2025] [Indexed: 05/24/2025]
Abstract
BACKGROUND AND AIM We investigated the association between fasting serum and urinary nitric oxide metabolite (NOx) levels and fatty liver index (FLI), a non-invasive surrogate of non-alcoholic fatty liver disease (NAFLD) and liver steatosis. METHOD This cross-sectional study included 598 adults (aged≥18 years, 48.6% men) who participated in the Tehran Lipid and Glucose Study (2015-2017). Serum and urine NOx concentrations were quantified using a spectrophotometric method following the Griess reaction. FLI values were calculated using γ-glutamyl transferase, triglycerides, body mass index, and waist circumference. The associations between urinary and serum NOx-to-creatinine (Cr) ratio [either as a categorical variable, i.e., tertiles, or as a continuous variable, i.e., per 1 SD) with NAFLD (i.e., FLI≥60) were assessed using multivariable-adjusted binary logistic regression. RESULTS The study participants' mean (SD) age was 42.5±14.6 y. The mean (SD) of serum and urinary NOx was 37.5±16.7 and 1310±751 μmol/L, respectively. The mean (SD) of FLI was 43.3±30.2, and the prevalence of NAFLD was 32.4%. Serum NOx-to-Cr ratio was not associated with the chance of having NAFLD (OR=1.66, 95% CI=0.98-2.82; P value=0.058). Higher urinary NOx-to-Cr ratio was significantly associated with a reduced probability of NAFLD (OR=0.61, 95% CI=0.38-0.95, and OR=0.54, 95% CI=0.34-0.87, in the second and third tertiles). CONCLUSION Higher dietary nitrate (NO3) intake, indicated by increased urinary NOx-to-Cr ratio, is associated with a reduced probability of NAFLD, highlighting the potential role of dietary NO3 in liver health.
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Affiliation(s)
- Zahra Bahadoran
- Micronutrient Research Center, Research Institute for Endocrine Disorders, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine Disorders, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Molecular Biology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Beyazal Polat H, Beyazal M, Arpa M, Kızılkaya B, Ayaz T, Gündoğdu ÖL, Konur K, Polat Z, Beyazal Çeliker F, Atasoy H. Exploring the Prevalence and Risk Factors of MASLD in Patients with Newly Diagnosed Diabetes Mellitus: A Comprehensive Investigation. J Clin Med 2025; 14:3513. [PMID: 40429507 PMCID: PMC12112127 DOI: 10.3390/jcm14103513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Revised: 04/22/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) represents a growing concern in the context of metabolic disorders, particularly among individuals diagnosed with type 2 diabetes mellitus (T2DM). This study aimed to investigate the prevalence of MASLD among newly diagnosed T2DM patients and identify the risk factors for MASLD in this population. Methods: This prospective study included 128 patients with newly diagnosed T2DM between January 2022 and June 2023. Demographic, clinical, anthropometric (BMI, waist circumference), and laboratory data (glucose, HbA1c, lipid profile, ALT, AST, creatinine, platelet count) were collected. MASLD was diagnosed based on ultrasonographic evidence of hepatic steatosis with at least one cardiometabolic risk factor after excluding other causes. Linear regression models were used to determine independent predictors. Results: MASLD was detected in 80.4% of patients. Compared with the MASLD (-) group, the MASLD (+) group had significantly higher ALT (47.1 ± 23 U/L vs. 24.9 ± 8 U/L, p < 0.001) and non-HDL cholesterol (189 ± 57 mg/dL vs. 167 ± 28 mg/dL, p = 0.047). Spearman correlation showed positive associations of MASLD severity with waist circumference, LDL cholesterol, and platelet count. ALT and BMI were independently associated with MASLD in linear regression analysis. Conclusions: This study underscores the significant prevalence of MASLD in newly diagnosed T2DM patients, emphasizing the relevance of early detection in addressing this common comorbidity in the diabetic population.
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Affiliation(s)
- Hatice Beyazal Polat
- Recep Tayyip Erdoğan University Faculty of Medicine, 53100 Rize, Türkiye; (M.B.); (M.A.); (B.K.); (T.A.); (Ö.L.G.); (K.K.); (F.B.Ç.); (H.A.)
| | - Mehmet Beyazal
- Recep Tayyip Erdoğan University Faculty of Medicine, 53100 Rize, Türkiye; (M.B.); (M.A.); (B.K.); (T.A.); (Ö.L.G.); (K.K.); (F.B.Ç.); (H.A.)
| | - Medeni Arpa
- Recep Tayyip Erdoğan University Faculty of Medicine, 53100 Rize, Türkiye; (M.B.); (M.A.); (B.K.); (T.A.); (Ö.L.G.); (K.K.); (F.B.Ç.); (H.A.)
| | - Bayram Kızılkaya
- Recep Tayyip Erdoğan University Faculty of Medicine, 53100 Rize, Türkiye; (M.B.); (M.A.); (B.K.); (T.A.); (Ö.L.G.); (K.K.); (F.B.Ç.); (H.A.)
| | - Teslime Ayaz
- Recep Tayyip Erdoğan University Faculty of Medicine, 53100 Rize, Türkiye; (M.B.); (M.A.); (B.K.); (T.A.); (Ö.L.G.); (K.K.); (F.B.Ç.); (H.A.)
| | - Ömer Lütfi Gündoğdu
- Recep Tayyip Erdoğan University Faculty of Medicine, 53100 Rize, Türkiye; (M.B.); (M.A.); (B.K.); (T.A.); (Ö.L.G.); (K.K.); (F.B.Ç.); (H.A.)
| | - Kamil Konur
- Recep Tayyip Erdoğan University Faculty of Medicine, 53100 Rize, Türkiye; (M.B.); (M.A.); (B.K.); (T.A.); (Ö.L.G.); (K.K.); (F.B.Ç.); (H.A.)
| | - Zehra Polat
- Rize Chambers and Commodity Exchanges Union Science High School, 53020 Rize, Türkiye;
| | - Fatma Beyazal Çeliker
- Recep Tayyip Erdoğan University Faculty of Medicine, 53100 Rize, Türkiye; (M.B.); (M.A.); (B.K.); (T.A.); (Ö.L.G.); (K.K.); (F.B.Ç.); (H.A.)
| | - Halil Atasoy
- Recep Tayyip Erdoğan University Faculty of Medicine, 53100 Rize, Türkiye; (M.B.); (M.A.); (B.K.); (T.A.); (Ö.L.G.); (K.K.); (F.B.Ç.); (H.A.)
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19
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Li R, Su K, Wu T, Xu L, Song W, Sun D, Zeng T, Chen J, Xin H, Li Y, Zang M, Hu M. Genome-wide enhancer-gene regulatory maps of liver reveal novel regulatory mechanisms underlying NAFLD pathogenesis. BMC Genomics 2025; 26:493. [PMID: 40375105 PMCID: PMC12082939 DOI: 10.1186/s12864-025-11668-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Accepted: 05/02/2025] [Indexed: 05/18/2025] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) represents the most widespread liver disease globally, ranging from non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH) to fibrosis/cirrhosis, with potential progression to hepatocellular carcinoma (HCC). Genome-wide association studies (GWASs) have identified several single nucleotide polymorphisms (SNPs) associated with NAFLD. However, numerous GWAS signals associated with NAFLD locate in non-coding regions, posing a challenge for interpreting their functional annotation. RESULTS In this study, we utilized the Activity-by-Contact (ABC) model to construct the enhancer-gene maps of liver by integrating epigenomic data from 15 liver tissues and cell lines. We constructed the most comprehensive genome-wide regulatory maps of the liver, identifying 543,486 enhancer-gene connections, including 267,857 enhancers and 16,872 target genes. Enrichment analyses revealed that the ABC SNPs are significantly enriched in active chromatin regions and active chromatin state. By combining the ABC regulatory maps and NAFLD GWAS data, we systematically identified ABC SNPs associated with NAFLD risk. Through the functional annotations, such as pathway enrichment and drug-gene interaction analyses, we identified 6 genes (GGT1, ACTG1, SPP1, EPHA2, PROZ and SHMT1) as candidate NAFLD genes, with SHMT1 previously reported. Among the SNPs connected to the candidate genes, the ABC SNP rs2017869 (odds ratio [OR] for the C allele = 1.10, 95% CI = 1.04-1.16, P = 5.97 × 10- 4) had the highest ABC score. According to the ABC maps, rs2017869 links to GGT1, and several drugs targeting this gene, such as liothyronine, showed potential benefits to patients with NAFLD. Furthermore, we identified that another novel gene, EPHA2, may play a crucial role in NAFLD by regulating the GGT levels. CONCLUSIONS Our study provides the most comprehensive ABC regulatory maps of the liver to date. This resource offers a valuable reference for identifying regulatory variants and prioritizing susceptibility genes of liver diseases, such as NAFLD.
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Affiliation(s)
- Ruofan Li
- Medical School of Chinese People's Liberation Army (PLA), 28 Fuxing Road, 100853, Beijing, China
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Kaiyan Su
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, 1,838 North Guangzhou Ave, Guangzhou, Guangdong, 510515, China
| | - Tianzhun Wu
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
| | - Li Xu
- Department of Hepatopancreatobiliary Surgery, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Wenyu Song
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China
| | - Dandan Sun
- Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Tao Zeng
- Medical School of Chinese People's Liberation Army (PLA), 28 Fuxing Road, 100853, Beijing, China
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Jinzhang Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, 1,838 North Guangzhou Ave, Guangzhou, Guangdong, 510515, China.
| | - Haibei Xin
- Department of Hepatobiliary Surgery, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
| | - Yuanfeng Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China.
| | - Mengya Zang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, 1,838 North Guangzhou Ave, Guangzhou, Guangdong, 510515, China.
| | - Minggen Hu
- Medical School of Chinese People's Liberation Army (PLA), 28 Fuxing Road, 100853, Beijing, China.
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, 28 Fuxing Road, Beijing, 100853, China.
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20
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Zhang Y, Ma T, Lu X, Hua H, Wu L, Chen Z. Mechanical mechanics-reclaiming a new battlefield for chronic liver disease. J Adv Res 2025:S2090-1232(25)00346-7. [PMID: 40379238 DOI: 10.1016/j.jare.2025.05.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Revised: 04/17/2025] [Accepted: 05/12/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND In the 21st century, significant breakthroughs have been made in the research of chronic liver disease. New biochemical markers of pathogenicity and corresponding drugs continue to emerge. However, current treatment strategies remain unsatisfactory due to complex pathological changes in the liver, including vascular dysfunction, myofibroblast-like transition, and local tissue necrosis in liver sinusoids. These challenges have created an urgent need for innovative, synergistic treatments. Mechanical mechanics is a growing field, with increasing evidence suggesting that mechanical signals play a role similar to that of biochemical markers. These signals influence response speed, conduction intensity, and functional diversity in regulating cell activities. AIM OF REVIEW This review summarizes the three main mechanical characteristics involved in the progression of "liver fibrosis-cirrhosis-hepatocellular carcinoma" and provides an in-depth interpretation of several mechanically-related targets. Finally, current and cutting-edge therapeutic strategies are proposed from a cellular perspective. Despite the many challenges that remain, this review is both relevant and significant.
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Affiliation(s)
- Yiheng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Tianle Ma
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - XingXing Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Haibing Hua
- Department of Gastroenterology, Jiangyin Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Jiangyin 214400, China.
| | - Li Wu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Zhipeng Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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21
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Qin J, Zhu W, Zhou W. Navigating the Paradox of IL-22: Friend or Foe in Hepatic Health? J Gastroenterol Hepatol 2025. [PMID: 40358483 DOI: 10.1111/jgh.16991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 03/11/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025]
Abstract
Interleukin-22 (IL-22), a cytokine from the IL-10 family produced by T cells and innate lymphoid cells, plays a crucial role in immune responses and tissue regeneration. Its association with liver disease has garnered significant attention; however, its exact impact remains controversial. This review aims to enhance the current understanding of the dual role of IL-22 in liver disease by exploring its protective and pathogenic effects. First, we provide an overview of IL-22 biology, including its source, receptors, and signaling pathways. Subsequently, we offer a comprehensive overview of the dual function of IL-22 in non-neoplastic liver disease, emphasizing its antiapoptotic and regenerative properties. We also discuss the applicability of the conclusions drawn from studies on nonalcoholic fatty liver disease to metabolic dysfunction-associated steatotic liver disease. Furthermore, we elaborate on the intricate role of IL-22 in hepatocellular carcinoma, particularly its influence on the tumor microenvironment, proliferation, and immune evasion. In conclusion, IL-22 is paradoxical in liver disease, acting as a friend and foe. It is imperative to understand this paradox to develop targeted therapies that capitalize on the beneficial effects of IL-22 while mitigating its detrimental effects.
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Affiliation(s)
- Jianqi Qin
- The Second Hospital of Lanzhou University, Department of General Surgery, Lanzhou University Second Clinical Medical College; Key Laboratory of Environmental Oncology of Gansu Province, Lanzhou, Gansu, China
| | - Weixiong Zhu
- The Second Hospital of Lanzhou University, Department of General Surgery, Lanzhou University Second Clinical Medical College; Key Laboratory of Environmental Oncology of Gansu Province, Lanzhou, Gansu, China
| | - Wence Zhou
- The Second Hospital of Lanzhou University, Department of General Surgery, Lanzhou University Second Clinical Medical College; Key Laboratory of Environmental Oncology of Gansu Province, Lanzhou, Gansu, China
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22
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Jiang Y, Jiang K, Sun P, Liu Y, Nie H. Oroxylin A ameliorates non-alcoholic fatty liver disease by modulating oxidative stress and ferroptosis through the Nrf2 pathway. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159628. [PMID: 40368273 DOI: 10.1016/j.bbalip.2025.159628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 04/26/2025] [Accepted: 05/10/2025] [Indexed: 05/16/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent and progressive liver disorder posing a global health challenge. Oroxylin A, a naturally occurring flavonoid, with a broad spectrum of pharmacological activities. This study aimed to explore the therapeutic potential of oroxylin A and unravel its molecular mechanisms in mitigating high-fat diet (HFD)-induced NAFLD in murine models. Wild-type (WT) and nuclear factor erythroid 2-related factor 2 knockout (Nrf2-/-) mice were administered a HFD to generate in vivo models, while free fatty acids-treated HepG2 cells served as the in vitro model. To investigate the effects of oroxylin A, serum and liver biochemical markers, hepatic histology, lipid metabolism, and oxidative stress were assessed in a NAFLD mouse model. The underlying mechanisms of oroxylin A were further explored through Western blotting, immunohistochemistry, and immunofluorescence analysis. Oroxylin A mitigated hepatic steatosis and injury by reducing liver index, AST, ALT, TG, and TC levels, improving histology, and restoring lipid metabolism. Glucose and insulin tolerance tests demonstrated improved glucose homeostasis and insulin sensitivity. Moreover, oroxylin A suppressed inflammation, apoptosis, and fibrosis, while enhancing antioxidant defenses, and improving mitochondrial function. Mechanistically, oroxylin A activated the Keap1/Nrf2/GPX4/SLC7A11 axis, upregulating Nrf2 and HO-1. These effects were abolished in Nrf2-/- mice. In vitro results were consistent, and molecular docking, dynamics simulations, and CETSA confirmed its direct Keap1 binding. Oroxylin A protects against NAFLD by modulating the Nrf2 pathway, reducing oxidative stress and ferroptosis, making it a promising candidate for clinical NAFLD therapy.
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Affiliation(s)
- Yuzi Jiang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, China
| | - Kangwei Jiang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, China
| | - Peilin Sun
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, China
| | - Yuan Liu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, China
| | - Hongming Nie
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, China.
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Xu M, Gong R, Xie J, Xu S, Wang S. Clinical characteristics of lean and non-lean non-alcoholic fatty liver disease: a cross-sectional study. Nutr Metab (Lond) 2025; 22:40. [PMID: 40355898 PMCID: PMC12070601 DOI: 10.1186/s12986-025-00927-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Accepted: 04/04/2025] [Indexed: 05/15/2025] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) affects more than a quarter of the global population and has become the world's number one chronic liver disease, seriously jeopardizing public life and health. Despite the new terminology of metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed, the mechanisms underlying the heterogeneity across BMI stratification in non-alcoholic fatty liver disease (NAFLD) remain unclear. The aim of this study was to reveal the differences in metabolic and fibrotic characteristics between lean (BMI < 23 kg/m2) and non-lean NAFLD in an Asian population. METHODS The current study collected NAFLD patients from the physical examination population. Patients were divided into two groups by BMI to compare their clinical parameters, including lean (BMI < 23 kg/m2) and non-lean (BMI ≥ 23 kg/m2) and fibrosis subgroups (with a threshold of LSM = 8 kPa) and analyzed for risk factors by logistic regression models. RESULTS Of the 11,577 NAFLD patients who participated in the study, there were 916 lean and 10,661 non-lean. The non-lean group was younger than the lean group (median age 50 vs. 52 years, P < 0.001) and had a significantly higher prevalence of hypertension (28.0% vs. 18.3%), diabetes mellitus (10.1% vs. 6.1%), and liver fibrosis (9.1% vs. 5.1%) (all P < 0.001). Analysis of metabolic indexes showed that TyG, TyG-BMI, TG/HDL-C and APRI were higher in the non-lean group (all P < 0.001). Gender stratification revealed that ALT was significantly higher in the male non-lean group, while HDL-C was lower in the female non-lean group (1.35 vs. 1.47 mmol/L). Multiple regression suggested that the risk of fibrosis was independently associated with CAP values and fasting glucose, BMI, direct bilirubin, globulin, and age in the non-lean group, whereas the risk was mainly driven by GGT and ALP in the lean group. CONCLUSIONS Non-lean NAFLD patients showed more significant metabolic disturbances and risk of liver fibrosis. Although metabolic indicators (TyG, FIB-4) have limited predictive value for liver fibrosis, they are strongly associated with metabolic risk in MASLD.
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Affiliation(s)
- Mengyan Xu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Rui Gong
- Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jiao Xie
- Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Sanping Xu
- Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Shi Wang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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24
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Hao Y, Li X, Zhang Y, Zheng J, Miao Y, Tan J, Zhang Q. Combined effect of fasting blood glucose and serum uric acid on nonalcoholic fatty liver disease. Lipids Health Dis 2025; 24:168. [PMID: 40340743 PMCID: PMC12060386 DOI: 10.1186/s12944-025-02538-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 03/17/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND This study sought to investigate the independent and synergistic impacts of fasting blood glucose (FBG) and serum uric acid (SUA) levels on non-alcoholic fatty liver disease (NAFLD) in participants with and without type 2 diabetes mellitus (T2DM). METHOD A total of 12,430 participants (mean age: 54.34 ± 15.23, 34.34% female) were enrolled through the Health Screening Center of Tianjin Medical University General Hospital. FBG was classified as < 6 mmol/L, 6-7 mmol/L, and ≥ 7 mmol/L. SUA was classified into two categories: normal SUA and hyperuricemia (SUA level ≥ 420 µmol/L for men, ≥ 360 µmol/L for women). T2DM was ascertained through self-reported data. The diagnosis of NAFLD is established via abdominal ultrasound imaging. Logistic regression models and interaction effect models are used for data analysis. RESULT Of the 12,430 participants, 4846 (38.99%) were diagnosed with NAFLD. In comparison to individuals with FBG < 6 mmol/L and no self-reported T2DM, those with FBG ≥ 7 mmol/L and no self-reported T2DM exhibited the highest prevalence of NAFLD (odds ratio [OR] 2.91, 95% CI 2.16-3.93) following multi-adjusted analysis. In the joint effect analysis of FBG and SUA, FBG ≥ 7 mmol/L and hyperuricemia were linked to a greater prevalence of NAFLD compared to FBG < 6 mmol/L and normal SUA, both in individuals with self-reported T2DM (OR 2.92, 95% CI 1.68-5.05) and those without self-reported T2DM (OR 7.87, 95% CI 3.57-17.34). An additive interaction existed between FBG and SUA regarding NAFLD in individuals without self-reported T2DM (AP 0.488, 95% CI: 0.068-0.909, P = 0.02). CONCLUSION Elevated FBG levels are associated with NAFLD irrespective of self-reported T2DM status. The concomitant elevation of FBG and SUA levels exhibits a significant correlation with NAFLD, particularly in individuals lacking self-reported T2DM.
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Affiliation(s)
- Yifan Hao
- Department of Geriatrics, Tianjin Medical University General Hospital, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in the Central Nervous System, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Elderly Health, Ministry of Education, Tianjin Geriatrics Institute, Tianjin, China
| | - Xuerui Li
- Department of Geriatrics, Tianjin Medical University General Hospital, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in the Central Nervous System, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Elderly Health, Ministry of Education, Tianjin Geriatrics Institute, Tianjin, China
| | - Yiting Zhang
- Department of Geriatrics, Tianjin Medical University General Hospital, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in the Central Nervous System, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Elderly Health, Ministry of Education, Tianjin Geriatrics Institute, Tianjin, China
| | - Jun Zheng
- Department of Geriatrics, Tianjin Medical University General Hospital, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in the Central Nervous System, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Elderly Health, Ministry of Education, Tianjin Geriatrics Institute, Tianjin, China
| | - Yuyang Miao
- Department of Geriatrics, Tianjin Medical University General Hospital, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in the Central Nervous System, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Elderly Health, Ministry of Education, Tianjin Geriatrics Institute, Tianjin, China
| | - Jin Tan
- Department of Geriatrics, Tianjin Medical University General Hospital, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in the Central Nervous System, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Elderly Health, Ministry of Education, Tianjin Geriatrics Institute, Tianjin, China
| | - Qiang Zhang
- Department of Geriatrics, Tianjin Medical University General Hospital, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in the Central Nervous System, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Elderly Health, Ministry of Education, Tianjin Geriatrics Institute, Tianjin, China.
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Key Laboratory of Elderly Health, Tianjin Geriatrics Institute, Anshan Road NO.154, Tianjin, 300052, China.
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25
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Liu B, Jia Y, Gu Z, Li Y, Zhou Y, Cao Y. Metabolic dysfunction associated steatotic liver disease is associated with an increased risk of multiple respiratory system diseases. Sci Rep 2025; 15:15937. [PMID: 40335623 PMCID: PMC12059187 DOI: 10.1038/s41598-025-96710-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 03/31/2025] [Indexed: 05/09/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a significant public health concern. However, the relationship between MAFLD and different types of respiratory diseases is not yet fully understood. In UK Biobank prospective cohort, 11 types of respiratory diseases were identified according to the ICD-10 codes. Cox regression was used to determine the association between MASLD and respiratory disease risk. A total of 393,416 subjects with an average age of 56.6 years were included, MASLD patients account for 34.9%. After fully adjustment for confounding factors, 9 out of 11 respiratory diseases were significantly associated with MASLD, including influenza (hazard ratio (HR): 1.294), pneumonia (HR: 1.258), chronic lower respiratory diseases (HR: 1.297), asthma (HR: 1.222), lung diseases due to external agents (HR: 1.190), interstitial lung diseases (HR: 1.336), diseases of the pleura (HR: 1.175), pulmonary embolism (HR: 1.225), lung and bronchus cancer (HR: 1.212) and respiratory system death (HR: 1.108) (P < 0.05 for all). The risk of respiratory diseases increases with the severity of MASLD assessed by fibrosis score. The relationship between the MASLD phenotype and respiratory diseases is independent of polygenic risk scores and four related risk alleles. These findings emphasize the value of comprehensive prevention of respiratory diseases by targeting MASLD.
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Affiliation(s)
- Bofu Liu
- Department of Emergency Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Institute of Disaster Medicine, Sichuan University, Chengdu, China
| | - Yu Jia
- West China Hospital, General Practice Ward/International Medical Center Ward, General Practice Medical Center, Sichuan University, Chengdu, China
| | - Zhihan Gu
- Department of Emergency Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Institute of Disaster Medicine, Sichuan University, Chengdu, China
| | - Yizhou Li
- West China Hospital, General Practice Ward/International Medical Center Ward, General Practice Medical Center, Sichuan University, Chengdu, China
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China School of Stomatology, National Center of Stomatology, Sichuan University, Chengdu, China
| | - Yiheng Zhou
- West China Hospital, General Practice Ward/International Medical Center Ward, General Practice Medical Center, Sichuan University, Chengdu, China
| | - Yu Cao
- Department of Emergency Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China.
- Institute of Disaster Medicine, Sichuan University, Chengdu, China.
- Department of Emergency Medicine, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, Sichuan, China.
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Deng D, Xie Y, Wang Y, Song W, Liu Y, Liu B, Guo H. Construction and validation of a nomogram for detecting chronic kidney disease in patients with nonalcoholic fatty liver disease: Insights from the NHANES database. Clinics (Sao Paulo) 2025; 80:100686. [PMID: 40339352 DOI: 10.1016/j.clinsp.2025.100686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 03/25/2025] [Accepted: 04/21/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND AND OBJECTIVES Fatty liver disease is often associated with renal impairment in many patients. Early detection and prompt intervention are crucial for improving patient quality of life and reducing mortality rates. This study aimed to develop and validate a nomogram for detecting the risk of Chronic Kidney Disease (CKD) comorbidity in adults with Nonalcoholic Fatty Liver Disease (NAFLD) in the United States. METHODS From the NHANES (2017‒2020) database, the authors enrolled 2848 NAFLD participants, of whom 633 also had CKD. The authors employed the Least Absolute Shrinkage and Selection Operator (LASSO) regression and multivariate logistic regression to identify variables with predictive value. The overlapping features were selected to construct a predictive model, which was presented as a nomogram. The effectiveness of the nomogram was evaluated using Receiver Operating Characteristic (ROC) curves, calibration plots, and decision curve analysis. RESULTS Six indicators were included in the model: age, systolic blood pressure, serum albumin, high-sensitivity C-reactive protein, total cholesterol, and triglycerides. The area under the curve of the nomogram for predicting CKD in the training set was 0.772, with a 95 % Confidence Interval (95 % CI) of 0.746 to 0.797. In the validation set, the area under the curve was 0.722, with a 95 % CI of 0.680 to 0.763. The calibration curve analyses demonstrated that the prediction outcomes of the model aligned well with the actual outcomes, indicating good clinical applicability. CONCLUSIONS The nomogram demonstrated excellent performance and has the potential to serve as an auxiliary tool for detecting CKD in NAFLD patients.
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Affiliation(s)
- Dazhang Deng
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, PR China; Laboratory of Hepatobiliary Surgery, the Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, PR China
| | - Yutong Xie
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, PR China
| | - Ya Wang
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, PR China
| | - Wanhan Song
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, PR China
| | - Yuguo Liu
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, PR China
| | - Bin Liu
- Laboratory of Hepatobiliary Surgery, the Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, PR China
| | - Honghui Guo
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, PR China; Laboratory of Hepatobiliary Surgery, the Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, PR China; Dongguan Key Laboratory for Development and Application of Experimental Animal Resources in Biomedical Industry, School of Public Health, Guangdong Medical University, Dongguan, PR China.
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Manolis AA, Manolis TA, Vouliotis A, Manolis AS. Metabolic dysfunction-associated steatotic liver disease and the cardiovascular system. Trends Cardiovasc Med 2025; 35:258-265. [PMID: 39848507 DOI: 10.1016/j.tcm.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/09/2025] [Accepted: 01/09/2025] [Indexed: 01/25/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty-liver disease, is an important and rising health issue with a link with atherosclerotic cardiovascular (CV) disease (CVD), affecting ∼25-30 % of the adults in the general population; in patients with diabetes, its prevalence culminates to ∼70 %; its evolutive form, nonalcoholic steatohepatitis, is estimated to be the main cause of liver transplantation in the future. MASLD is a multisystem disease that affects, besides the liver, extra-hepatic organs and regulatory pathways; it raises the risk of type 2 diabetes mellitus (T2D), CVD, and chronic kidney disease; the disease may also progress to hepatocellular carcinoma. Its diagnosis requires hepatic steatosis and at least one cardiometabolic risk factor and the exclusion of both significant alcohol consumption and other competing causes of chronic liver disease. Beyond CV events, associated metabolic comorbidities comprise obesity (∼50 %), T2D (∼20 %), hyperlipidemia (∼70 %), hypertension (∼40 %), and metabolic syndrome (∼40 %). Among the various clinical events, CV events mostly determine prognosis as they are the leading cause of death in these patients. Regarding management, statins exert beneficial effects in improving liver injury; silybin, derived from Silybum marianum, has some protective effects; lifestyle modification, such as weight loss, dietary changes, physical exercise, and abstention from alcohol use combined with optimal management of comorbidities are most helpful. Bariatric surgery may be an option in persons with MASLD and obesity. Adults with non-cirrhotic MASLD and significant liver fibrosis may be candidates for targeted treatment with resmetirom, which has histological efficacy on steatohepatitis and fibrosis with an acceptable safety and tolerability profile, whereas, no MASLD-targeted pharmacotherapy can be beneficial in the cirrhotic stage, whereby other measures may include metabolic drugs, nutritional counseling, surveillance for portal hypertension and hepatocellular carcinoma, and finally, liver transplantation in decompensated cirrhosis.
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Affiliation(s)
| | - Theodora A Manolis
- Department of Psychiatry, Aiginiteio University Hospital. Athens, Greece
| | | | - Antonis S Manolis
- Department of Cardiology, Euroclinic Hospital, Athens, Greece; First Department of Cardiology, Athens University School of Medicine, Athens, Greece.
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Qi W, Cao X, Chen Y, Chen H, Zhang N, Liu R, Wang W, Liu Q, Zheng S, Li S, Li X, Zao X, Ye Y. JiGuCao capsule formula alleviates metabolic fatty liver disease by regulating the gut-liver axis and lipid metabolism. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156559. [PMID: 40064115 DOI: 10.1016/j.phymed.2025.156559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 02/12/2025] [Accepted: 02/22/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND Metabolic-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition globally, characterized by suboptimal treatment outcomes. Traditional therapies often fail to address the multifaceted pathogenesis of MAFLD, which involves lipid metabolism, inflammation, and gut-liver axis dysregulation. JiGuCao Capsule formula (JCF), a patented Chinese medicine, has demonstrated clinical efficacy in liver disease treatment, indicating its potential as a new therapeutic option for MAFLD. PURPOSE This study aimed to investigate the therapeutic effects and underlying mechanisms of JCF in treating MAFLD, particularly focusing on its impact on liver pathology, intestinal health, and gut microbiota composition. METHODS A MAFLD mouse model was developed by administering a high-fat diet and 5% fructose water for 16 weeks. At week 8, mice exhibited significant steatosis, inflammation, and insulin resistance. Fifty mice were allocated into two groups: the normal diet (ND) group with 19 mice and the high-fat feed diet (HFD) group with 31 mice. Seven mice from each group were sacrificed at week 8 for serological and histopathological assessments. The remaining mice were allocated into ND (n = 6), HFD (n = 6), HFD + JCFL (human equivalent dose,780 mg/kg, n = 6), HFD + JCFH (threefold the human equivalent dose, 2340 mg/kg, n = 6), HFD + Polyene Phosphatidylcholine (PPC) (human equivalent dose,177.84 mg/kg, n = 6) and ND+ JCF (human equivalent dose,780 mg/kg, n = 6) groups. Daily gavage started at week 9. At week 16, after fasting, body weight and liver condition were recorded, and mice were euthanized with pentobarbital sodium. Mouse tissues and feces were collected for histopathological, molecular biological, and multi-omics analyses. RESULTS JCF effectively slowed MAFLD progression in mice by decreasing hepatic lipid accumulation and inflammation. Treatment with JCF significantly reduced hepatic triglycerides and inflammatory markers, including TNF-α and IL-6. JCF enhanced lipid metabolism, repaired the intestinal barrier, and lowered inflammatory cytokines in the intestines, as indicated by reduced serum LPS and restored tight junction proteins expression, such as claudin-1 and occludin. Fecal microbiota analysis indicated that JCF treatment elevated Lactobacillus levels and reduced Colidextribacter levels, correlating with enhanced metabolic profiles. The primary bioactive compounds identified in JCF responsible for these therapeutic effects were betulinic acid, cholic acid, deoxycholic acid, oleanolic acid, and pectolinarigenin. Transcriptomic analysis showed that JCF regulated key pathways involved in lipid metabolism, including the pparγ-cd36 axis and modulation of ox-LDL levels. The results indicate that JCF effectively mitigates MAFLD by influencing the gut-liver axis and lipid metabolism. CONCLUSION JCF alleviates MAFLD by modulating the gut-liver axis and lipid metabolism. Its effects involve improving gut barrier function, regulating microbiota, and targeting the pparγ-cd36 axis. Active compounds like betulinic acid support its therapeutic potential. JCF shows promise as a novel treatment for MAFLD, with further clinical studies needed.
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Affiliation(s)
- Wenying Qi
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Xu Cao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Yue Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Hening Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Ningyi Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Ruijia Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Wei Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Qiyao Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China; Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Shihao Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Size Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Xiaoke Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China; Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100700, PR China.
| | - Yong'an Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China; Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100700, PR China.
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Byrne CD, Armandi A, Pellegrinelli V, Vidal-Puig A, Bugianesi E. Μetabolic dysfunction-associated steatotic liver disease: a condition of heterogeneous metabolic risk factors, mechanisms and comorbidities requiring holistic treatment. Nat Rev Gastroenterol Hepatol 2025; 22:314-328. [PMID: 39962331 DOI: 10.1038/s41575-025-01045-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/27/2025] [Indexed: 03/09/2025]
Abstract
Μetabolic dysfunction-associated steatotic liver disease (MASLD) comprises a heterogeneous condition in the presence of steatotic liver. There can be a hierarchy of metabolic risk factors contributing to the severity of metabolic dysfunction and, thereby, the associated risk of both liver and extrahepatic outcomes, but the precise ranking and combination of metabolic syndrome (MetS) traits that convey the highest risk of major adverse liver outcomes and extrahepatic disease complications remains uncertain. Insulin resistance, low-grade inflammation, atherogenic dyslipidaemia and hypertension are key to the mechanisms of liver and extrahepatic complications. The liver is pivotal in MetS progression as it regulates lipoprotein metabolism and secretes substances that affect insulin sensitivity and inflammation. MASLD affects the kidneys, heart and the vascular system, contributing to hypertension and oxidative stress. To address the global health burden of MASLD, intensified by obesity and type 2 diabetes mellitus epidemics, a holistic, multidisciplinary approach is essential. This approach should focus on both liver disease management and cardiometabolic risk factors. This Review examines the link between metabolic dysfunction and liver dysfunction and extrahepatic disease outcomes, the diverse mechanisms in MASLD due to metabolic dysfunction, and a comprehensive, personalized management model for patients with MASLD.
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Affiliation(s)
- Christopher D Byrne
- National Institute for Health and Care Research, Southampton Biomedical Research Centre, University Hospital Southampton and University of Southampton, Southampton, UK
| | - Angelo Armandi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Vanessa Pellegrinelli
- Institute of Metabolic Science, MRC MDU Unit, University of Cambridge, Cambridge, UK
- Centro de Investigacion Principe Felipe, Valencia, Spain
| | - Antonio Vidal-Puig
- Institute of Metabolic Science, MRC MDU Unit, University of Cambridge, Cambridge, UK
- Centro de Investigacion Principe Felipe, Valencia, Spain
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy.
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Lei K, Chen Y, Wu J, Lin Y, Bai Y, Cao H, Che Q, Guo J, Su Z. Mechanism of liver x receptor alpha in intestine, liver and adipose tissues in metabolic associated fatty liver disease. Int J Biol Macromol 2025; 307:142275. [PMID: 40112983 DOI: 10.1016/j.ijbiomac.2025.142275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/16/2025] [Accepted: 03/17/2025] [Indexed: 03/22/2025]
Abstract
Metabolism associated fatty liver disease (MAFLD) has emerged as a growing global health challenge with limited effective treatments. Research on nuclear receptors offers promising new therapeutic avenues for MAFLD. The liver X receptor (LXR) has gained attention for its roles in tumors and metabolic and inflammatory diseases; However, its effects on MAFLD treatment remain a subject of debate. This review explores the therapeutic role of LXRα in MAFLD, focusing on its functions in the intestine, hepatic and adipose tissue, and summarizes recent advancements in LXRα ligands over the past five years. In the intestine, LXRα activation enhances the efflux of non-biliary cholesterol and reduces inflammation in the gut-liver axis by regulating intestinal high-density lipoprotein synthesis and its interaction with lipopolysaccharide. In the liver, LXRα activation facilitates cholesterol transport, influences hepatic lipid synthesis, and exerts anti-inflammatory effects. In adipose tissue, LXRα helps delay MAFLD progression by managing lipid autophagy and insulin resistance. Ligands that modulate LXRα transcriptional activity show considerable promise for MAFLD treatment.
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Affiliation(s)
- Kaiwen Lei
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Chen
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jianxing Wu
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yiyu Lin
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd, Science City, Guangzhou 510663, China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Souza M, Al-Sharif L, Diaz I, Mantovani A, Villela-Nogueira CA. Global Epidemiology and Implications of PNPLA3 I148M Variant in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-analysis. J Clin Exp Hepatol 2025; 15:102495. [PMID: 39882540 PMCID: PMC11773032 DOI: 10.1016/j.jceh.2024.102495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 12/18/2024] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND & AIMS PNPLA3 rs738409 variant is a risk factor for onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess its global prevalence, clinical and histological characteristics, and long-term outcomes in patients with MASLD. METHODS PubMed and Embase databases were searched until December 30, 2023, for observational studies on PNPLA3 genotyped adults with MASLD. Proportions were pooled using a generalized linear mixed model with Clopper-Pearson intervals. Continuous and dichotomous variables were analyzed using the DerSimonian-Laird method. International Prospective Register of Systematic Reviews registration number: CRD42023449838. RESULTS A total of 109 studies involving 118,302 individuals with MASLD were identified. The overall minor allele frequency of the G allele [MAF(G)] at PNPLA3 was 0.45 (95% confidence interval [CI]: 0.43; 0.48) with high heterogeneity (I2 = 98%). The highest MAF(G) was found in Latin America (0.63) and the lowest in Europe (0.38). No African countries were identified. Carriers of the PNPLA3 variant had reduced adiposity, altered fat metabolism, and worse liver damage/histology than noncarriers. There was significant heterogeneity in the clinical/histological analyses (I2 > 50%). Only the PNPLA3 GG genotype was associated with higher mortality and liver-related events with no heterogeneity (I2 = 0%). Metaregressions showed the influence of adiposity, age, diabetes mellitus, and glucose on some PNPLA3 expression parameters. Overall, there was a moderate risk of bias in the included studies. CONCLUSIONS This study reveals the global pattern of PNPLA3 and its clinical, histological, and outcome implications in MASLD. Patients with MASLD and PNPLA3 variant have different clinical features and worse liver severity, and only PNPLA3 GG has a higher risk of mortality and liver outcomes. Our findings highlight the importance of PNPLA3 genotyping in clinical trials and advocate for personalized medicine approaches.
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Affiliation(s)
- Matheus Souza
- Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Ivanna Diaz
- Department of Internal Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY, United States
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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Zhang M, Ji J, Lei Y, Qin F, Tao Y, Li N, Bian J, Li Z, Lai M, Qiu Z. Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement. Pharmacol Res 2025; 215:107706. [PMID: 40127788 DOI: 10.1016/j.phrs.2025.107706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/28/2025] [Accepted: 03/18/2025] [Indexed: 03/26/2025]
Abstract
Inhibiting de novo lipogenesis (DNL) in hepatocytes is a promising strategy for treating metabolic fatty liver diseases. ACLY, a key enzyme in the DNL pathway, has become a therapeutic target for non-alcoholic fatty liver disease (NAFLD). However, its inhibition shows mixed outcomes, depending on interventions and diets. Evidence suggests ACLY inhibition activates the ACSS2-mediated acetate metabolism and the subsequent DNL, though potential mechanisms and possible consequences remain unclear. This study found that targeting hepatic ACLY with AAV8-shRNA failed to improve NAFLD in mice fed a high-fat, high-fructose diet. Instead, it worsened inflammation and liver injury. ACLY inhibition conditionally upregulated DNL enzymes, but consistently activated the ACSS2-acetyl-CoA pathway and suppressed fatty acid oxidation. Further, ACLY inhibition led to polyunsaturated fatty acid accumulation, triggering mitochondrial dysfunction. The resulting ROS redirected carbon flux into acetate, activating the ACSS2-acetyl-CoA pathway, which promoted lipid biosynthesis and exacerbated mitochondrial dysfunction-a vicious cycle that fueled inflammation and liver damage. Dual inhibition of ACLY and ACSS2 broke this cycle by reducing hepatic acetyl-CoA flux, suppressing DNL, enhancing fatty acid oxidation via PPAR-α activation, and improving mitochondrial function. This combined targeting strategy reduced lipid accumulation, alleviated inflammation, and normalized aminotransferase levels, effectively reversing NAFLD progression.
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Affiliation(s)
- Mengdi Zhang
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jinliang Ji
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yuanyuan Lei
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Fujian Qin
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yitong Tao
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Ning Li
- National Experimental Teaching Demonstration Center of Pharmacy, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jinlei Bian
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Zhiyu Li
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Maode Lai
- School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China; Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Zhixia Qiu
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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Geng Y, Luo K, Stam J, Oosterhuis D, Gorter AR, van den Heuvel M, Crescitelli R, de Meijer VE, Wolters JC, Olinga P. Characterization of Extracellular Vesicles Derived From Human Precision-Cut Liver Slices in Metabolic Dysfunction-Associated Steatotic Liver Disease. JOURNAL OF EXTRACELLULAR BIOLOGY 2025; 4:e70043. [PMID: 40313415 PMCID: PMC12042696 DOI: 10.1002/jex2.70043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/30/2025] [Accepted: 02/28/2025] [Indexed: 05/03/2025]
Abstract
Extracellular vesicles (EVs) are cell-produced, membrane-surrounded vesicles that harbour the biological features of donor cells. In the current study, we are the first to isolate and characterize EVs isolated from human precision-cut liver slices (PCLS), obtained from both healthy and metabolic dysfunction-associated steatohepatitis (MASH) cirrhotic livers. PCLS derived from patients can faithfully represent disease conditions in humans. EVs were isolated from human PCLS after incubating in normal medium or modified medium that mimics the pathophysiological environment of metabolic dysfunction associated liver disease (MASLD). MASH PCLS produced higher amounts of EVs compared to healthy PCLS (p < 0.001). Mass spectrometry revealed that around 300 proteins were significantly different in EVs derived from MASH PCLS versus healthy PCLS (FDR < 0.05), irrespective of the type of medium. Significantly changed EV proteins were largely involved in signalling receptor binding function and showed potential in promoting fibrosis. In the liver, these ligand-associated receptors are highly expressed in hepatic stellate cells, and the MASH EVs functionally promoted the activation of hepatic stellate cells. Furthermore, the amounts of EpCAM and ITGA3 in EVs were positively associated with the progression of MASLD, which suggests the use of liver-derived EVs as potential biomarkers for MASLD. Characterization of EVs derived from human PCLS may assist future studies in investigating the pathogenesis and identifying liver-specific EVs as biomarkers of MASLD.
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Affiliation(s)
- Yana Geng
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of PharmacyUniversity of GroningenGroningenthe Netherlands
| | - Ke Luo
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of PharmacyUniversity of GroningenGroningenthe Netherlands
| | - Janine Stam
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of PharmacyUniversity of GroningenGroningenthe Netherlands
- Department of Analytical Biochemistry, Groningen Research Institute of PharmacyUniversity of GroningenGroningenthe Netherlands
| | - Dorenda Oosterhuis
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of PharmacyUniversity of GroningenGroningenthe Netherlands
| | - Alan R. Gorter
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of PharmacyUniversity of GroningenGroningenthe Netherlands
| | - Marius van den Heuvel
- Division of Pathology, Department of Pathology and Medical BiologyUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Rossella Crescitelli
- Department of Surgery, Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational Medicine, Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGöteborgSweden
| | - Vincent E. de Meijer
- Department of Surgery, Section of Hepatobiliary Surgery & Liver TransplantationUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Justina C. Wolters
- Department of PediatricsUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of PharmacyUniversity of GroningenGroningenthe Netherlands
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Momeni S, Hajizadeh-Sharafabad F, Pashaei MR. Adherence to the Dietary Approaches to Stop Hypertension diet was associated with the risk of nonalcoholic fatty liver disease: A systematic review and meta-analysis of observational studies. Nutr Res 2025; 137:14-21. [PMID: 40188580 DOI: 10.1016/j.nutres.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/10/2025] [Accepted: 03/10/2025] [Indexed: 04/08/2025]
Abstract
The Dietary Approaches to Stop Hypertension (DASH) diet has long been recommended for the management of hypertension, while it may provide other metabolic benefits. This study aimed to analyze the association between the DASH diet and nonalcoholic fatty liver disease (NAFLD) risk through a systematic review and meta-analysis. We hypothesized that the adherence to DASH diet is inversely associated with NAFLD risk. PubMed, Web of Science, Scopus, and Google Scholar were searched to find relevant publications up to September 2024. We included observational studies evaluating the association between the DASH diet score and the risk of NAFLD. Pooling effect sizes was conducted using a random effects model to determine the odd ratio (OR) of incident NAFLD associated with the DASH diet. Eight studies with a total of 120937 participants were included in the meta-analysis. The pooled OR for NAFLD in the highest score of the DASH diet vs. lowest score was 0.78 (95% CI: 0.70-0.86, P < .001), indicating a significant inverse association between the DASH diet and NAFLD risk. The result was stable to sensitivity analysis. A significant heterogeneity was observed between studies (I2=62.7%, P = .009). Overall, this meta-analysis showed that individuals with the highest score of the DASH diet were 22% less likely to have NAFLD in comparison to those with the lowest score of the DASH diet, independent of body mass index. Further high-quality prospective studies are needed to confirm the protective effect of the DASH diet on NAFLD.
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Affiliation(s)
- Sadra Momeni
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Mohammad Reza Pashaei
- Patient Safety Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of Internal Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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35
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Cao R, Zhang Y, Cao L, Jiang H. Is type 2 diabetes a link between lung function and metabolic dysfunction-associated steatotic liver disease? Insights from population studies and Mendelian randomization. Eur J Gastroenterol Hepatol 2025; 37:652-659. [PMID: 39976012 DOI: 10.1097/meg.0000000000002941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
AIM This study aimed to investigate the relationship between lung function and metabolic dysfunction-associated steatotic liver disease (MASLD), and the potential mediating role of type 2 diabetes. METHODS Data from the 2007 to 2012 National Health and Nutrition Examination Survey were used. Logistic regression analysis was employed to assess the association between lung function parameters [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), FEV 1 /FVC] and MASLD prevalence while exploring type 2 diabetes mediation. Further analyses included linkage disequilibrium score regression, Mendelian randomization, and meta-analysis to examine the causal relationship between lung function and MASLD, considering type 2 diabetes mediation. RESULTS The results showed that higher FVC and FEV 1 levels were associated with decreased MASLD risk, with type 2 diabetes partially mediating this relationship. Genetic analyses supported a causal link between lung function and MASLD, with type 2 diabetes acting as an intermediary. However, no significant association was found between FEV 1 /FVC and MASLD. CONCLUSION The study identified a causal relationship between lung function and MASLD, with type 2 diabetes playing a partial mediating role.
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Affiliation(s)
- Runmin Cao
- Graduate School, Jinzhou Medical University (Jinzhou Central Hospital), Jinzhou, Liaoning Province
| | - Yurun Zhang
- Department of Rehabilitation Therapy, Shandong Xiandai University, Jinan, Shandong Province
| | - Ling Cao
- Department of Chronic Disease Prevention and Control, Jieshou City Center for Disease Control and Prevention, Fuyang
| | - Honghe Jiang
- Department of Clinical Medicine, Anhui University of Science and Technology, Huainan, Anhui Province, China
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Fernández-Quintela A, Laveriano-Santos EP, Portolés T, Gual-Grau A, Sancho JV, Portillo MP. Changes in Liver Metabolome Induced by Pterostilbene and Resveratrol in a Rat Model of Liver Steatosis. Mol Nutr Food Res 2025:e70078. [PMID: 40304525 DOI: 10.1002/mnfr.70078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 03/24/2025] [Accepted: 04/02/2025] [Indexed: 05/02/2025]
Abstract
To gain more light on the effects of resveratrol and pterostilbene in the hepatic metabolic modifications in an in vivo model of diet-induced hepatic steatosis, and to explore their relationships with gut microbiota by untargeted metabolomics and metagenomics. Rats were divided into five groups receiving either a standard diet or a high-fat high-fructose (HFHF) diet supplemented or not with pterostilbene (15 or 30 mg/kg body weight/day; PT15 or PT30 groups, respectively) or resveratrol (30 mg/kg body weight/day; RSV30 group). Supplementation with the stilbenes reduced the hepatic steatosis induced by the HFHF diet. After the metabolomics study, 27 differentially expressed metabolites showed variable importance in projection scores > 1 and could be considered as potential biomarkers. Therefore, based on the pathway enrichment analysis, "riboflavin metabolism" and "nicotinate and nicotinamide metabolism" revealed significant enrichment. Further, riboflavin showed positive correlations to Eubacterium and Faecalibacterium, and negative correlations to Lactobacillus and Oscillospira genera. Nicotinamide mononucleotide was only positively correlated to the Ralstonia genus. The untargeted metabolomics approach showed that the actions of resveratrol or pterostilbene on the prevention of liver steatosis are mediated by specific mechanisms of action. Particularly, pterostilbene, but not resveratrol, is suggested to significantly enrich riboflavin or nicotinate and nicotinamide metabolic pathways.
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Affiliation(s)
- Alfredo Fernández-Quintela
- Faculty of Pharmacy, Nutrition and Obesity Group, Department of Nutrition and Food Science, University of the Basque Country (UPV/EHU), Lucio Lascaray Research Centre, Vitoria-Gasteiz, Spain
- BIOARABA Institute of Health, Vitoria-Gasteiz, Spain
- CIBERobn Physiopathology of Obesity and Nutrition, Institute of Health Carlos III (ISCIII), Vitoria-Gasteiz, Spain
| | | | - Tania Portolés
- Enviromental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water (IUPA), Universitat Jaume I, Castellón de la Plana, Spain
| | - Andreu Gual-Grau
- Nutrigenomics and Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, Tarragona, Spain
| | - Juan Vicente Sancho
- Enviromental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water (IUPA), Universitat Jaume I, Castellón de la Plana, Spain
| | - Maria P Portillo
- Faculty of Pharmacy, Nutrition and Obesity Group, Department of Nutrition and Food Science, University of the Basque Country (UPV/EHU), Lucio Lascaray Research Centre, Vitoria-Gasteiz, Spain
- BIOARABA Institute of Health, Vitoria-Gasteiz, Spain
- CIBERobn Physiopathology of Obesity and Nutrition, Institute of Health Carlos III (ISCIII), Vitoria-Gasteiz, Spain
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Zhao X, Xia F, Dong Z, Huang W, Kong X, Cui Z, Yan M, Gao H, Rong R, Wang M, Liu G, Zhang Z, Zhang J, Yuan T, Cai H, Yan Z, Zhu L, Qin W. A novel EndMT inhibitor, xanthotoxin, attenuates non-alcoholic fatty liver disease by acting as TGFβR2 antagonist. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 143:156823. [PMID: 40347928 DOI: 10.1016/j.phymed.2025.156823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 04/12/2025] [Accepted: 04/29/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Endothelial-to-mesenchymal transition (EndMT) has emerged as a key process contributing to the pathology of non-alcoholic fatty liver disease (NAFLD). Thus, identifying EndMT inhibitors may help impede NAFLD progression. PURPOSE Our research aims to identify potent natural EndMT inhibitors and explore their therapeutic potential and mechanisms of action in NAFLD. METHODS A natural compound library was employed to screen potential EndMT inhibitors. High-fat diet (HFD)-induced ApoE-/- mice and free fatty acid (FFA)-treated human hepatic sinusoidal endothelial cells (HHSECs) were employed as animal and cellular models of NAFLD. EndMT was evaluated by western blotting, qRT-PCR, immunofluorescence staining, tube formation, wound healing, and transwell assays. LC-MS/MS was applied to screen for altered secreted proteins during EndMT. Molecular docking, CETSA, and SPR assays were employed to validate the combination of xanthotoxin with TGFβR2. RESULTS Xanthotoxin was identified as a novel EndMT inhibitor. Further investigation revealed that xanthotoxin ameliorates NAFLD in ApoE-/- mice. By inhibiting EndMT, xanthotoxin improves endothelial dysfunction, reduces the pro-NAFLD factor ANGPTL2 secretion, and increases the anti-NAFLD factor SOD2 secretion, thus reducing hepatocyte steatosis, inflammation, and hepatic stellate cell fibrosis. Additional studies demonstrated that xanthotoxin binds to TGFβR2 and acts as its antagonist to block EndMT. In mice, EC-specific overexpression of TGFβR2 negated xanthotoxin's therapeutic impact on NAFLD. CONCLUSION This study reveals for the first time that xanthotoxin attenuates NAFLD by acting as a TGFβR2 antagonist to inhibit EndMT. These findings highlight the significant therapeutic potential of xanthotoxin in NAFLD treatment.
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Affiliation(s)
- Xiaona Zhao
- School of Pharmacy, Shandong Second Medical University, Weifang 261000, Shandong, China; School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China
| | - Fangjie Xia
- School of Pharmacy, Shandong Second Medical University, Weifang 261000, Shandong, China; School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China
| | - Zixu Dong
- School of Pharmacy, Shandong Second Medical University, Weifang 261000, Shandong, China; School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China
| | - Wenyang Huang
- School of Pharmacy, Shandong Second Medical University, Weifang 261000, Shandong, China; School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China
| | - Xinxin Kong
- School of Pharmacy, Shandong Second Medical University, Weifang 261000, Shandong, China; School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China
| | - Zhoujun Cui
- Department of General Surgery, Rizhao People's Hospital, Rizhao 276800, China
| | - Maocai Yan
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China
| | - Honggang Gao
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China
| | - Ruixue Rong
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China; School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250000, Shandong, China
| | - Minghui Wang
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China; School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250000, Shandong, China
| | - Guoqing Liu
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China; School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250000, Shandong, China
| | - Zejin Zhang
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China; School of Pharmacy, Binzhou Medical University, Yantai 264000, Shandong, China
| | - Jing Zhang
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China
| | - Tao Yuan
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China; School of Pharmacy, Shandong First Medical University, Jinan 250000, Shandong, China
| | - Huiying Cai
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China; School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250000, Shandong, China
| | - Zhenzhen Yan
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China; School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250000, Shandong, China
| | - Lin Zhu
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China; School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250000, Shandong, China
| | - Wei Qin
- School of Pharmacy, Jining Medical University, Rizhao 276800, Shandong, China; Department of Cardiology (Shandong Provincial Key Laboratory for Cardiovascular Disease Diagnosis and Treatment) at Affiliated Hospital of Jining Medical University, Jining Medical University, Jining 272000, Shandong, China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Jinan 250000, Shandong, China.
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Yang CJ, Lin YC, Wu HC, Yen CH, Lin CH, Kuo YH, Chang HS. Flavonoid-Sesquiterpenoid Hybrids from the Leaves of Syzygium simile and Their Anti-Lipid Droplet Accumulation Activities. JOURNAL OF NATURAL PRODUCTS 2025; 88:1057-1067. [PMID: 40196987 PMCID: PMC12038841 DOI: 10.1021/acs.jnatprod.5c00157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/20/2025] [Accepted: 03/26/2025] [Indexed: 04/09/2025]
Abstract
Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of hepatic disorders characterized by excessive lipid accumulation in the liver with a global prevalence rate of 30%. Despite their increasing prevalence, current therapeutic interventions remain suboptimal, constrained by substantial adverse effects and prohibitive treatment costs. Through an anti-lipid droplet (LD) accumulation screening platform, over 3000 methanolic extracts of Formosan plants were evaluated. Among them, the leaf extract of Syzygium simile demonstrated significant inhibitory activity of 40% at 25 μg/mL, emerging as the most promising species. Through bioassay-guided fractionation, 20 compounds were isolated from the n-hexane layer of the leaves, including nine new compounds [simisyzygins C-G (1-5, respectively) and simicadinenes A-D (6-9, respectively)] and 11 known compounds. These new compounds possess unique carbon skeletons characterized as flavonoid-sesquiterpenoid hybrids. Their structures were elucidated by the analysis of spectroscopic data. The structures of 1, 4, 5, and 11 were further confirmed by single-crystal X-ray diffraction analysis. Syzygioblane B (11) demonstrated the most potent inhibition of LD accumulation in Huh7 cells, achieving a 64.1% reduction at 40 μM with dose-dependency (5-40 μM) and no observable cytotoxicity. This is the first phytochemical and biological investigation of S. simile that highlights its potential as a promising botanical drug candidate for treating LD accumulation-related diseases.
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Affiliation(s)
- Ching-Ju Yang
- School
of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department
of Pharmacy, Kaohsiung Municipal Siaogang
Hospital, Kaohsiung 812, Taiwan
| | - Yu-Chun Lin
- School
of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ho-Cheng Wu
- School
of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department
of Medical Research, Kaohsiung Medical University
Hospital, Kaohsiung 807, Taiwan
| | - Chia-Hung Yen
- Graduate
Institute of Natural Products, Kaohsiung
Medical University, Kaohsiung 807, Taiwan
- Drug
Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chu-Hung Lin
- Biomedical
Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 310, Taiwan
| | - Yueh-Hsiung Kuo
- Department
of Chinese Pharmaceutical Sciences and Chinese Medicine Resources,
Chinese Medicine Research Center, China
Medical University, Taichung 404, Taiwan
- Department
of Biotechnology, Asia University, Taichung 413, Taiwan
| | - Hsun-Shuo Chang
- School
of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department
of Medical Research, Kaohsiung Medical University
Hospital, Kaohsiung 807, Taiwan
- Drug
Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Wang Y, Wang H, Li Q, Zhang Y, Dai R, Wu J, Zhang Y, Zhang X, Zhao L, Liu J. Identification of Novel Cyclobutane-Based Derivatives as Potent Acetyl-CoA Carboxylase Allosteric Inhibitors for Nonalcoholic Steatohepatitis Drug Discovery. J Med Chem 2025; 68:8578-8599. [PMID: 40227434 DOI: 10.1021/acs.jmedchem.5c00259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025]
Abstract
Nonalcoholic steatohepatitis (NASH) has become a leading cause of liver fibrosis and hepatocellular carcinoma; however, there are no efficient drugs for NASH therapy. Acetyl-CoA carboxylase (ACC) is a crucial enzyme regulating lipid metabolism that is considered as a potential target for NASH treatment. Allosteric inhibitors target nonfunctional sites, which tend to be highly variable in protein families; thus, allosteric inhibitors are explored as an important source of drug candidates. Herein, several hotspot residues are initially identified by utilizing molecular dynamic simulation, MM-GBSA calculation, and alanine mutation. Then, focusing on the interaction with hotspot residues, several cyclobutane-based ACC allosteric inhibitors are designed, synthesized, and biologically evaluated. Among them, B1 demonstrates potent ACC inhibitory activity in vitro, a higher distribution in liver than in other tissues, and a potent therapeutic effect for NASH in vivo, making it a promising candidate for the treatment of NASH.
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Affiliation(s)
- Yazhou Wang
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Hai Wang
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Qingqing Li
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ying Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Rupeng Dai
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jun Wu
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Yanan Zhang
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Xiaomeng Zhang
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Liwen Zhao
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Jian Liu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
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Liu X, Sun H, Han Q, Wang Z, Zeng J, Liu J, Ou S, Jin K, Shao Y, Li D, Gao Z, Wang F. Gut microbiota-derived UDCA enhanced by metformin inhibits FXR to activate autophagy against MCD diet-induced NAFLD in mice. Int Immunopharmacol 2025; 153:114471. [PMID: 40121741 DOI: 10.1016/j.intimp.2025.114471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 02/19/2025] [Accepted: 03/09/2025] [Indexed: 03/25/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD), a prevalent chronic liver disease, poses a substantial global health burden. Metformin is known for its protective effects in NAFLD, but the role of gut microbiota in the underlying mechanisms remains unclear. In this study, metformin was found to mitigate methionine-choline deficient (MCD) -diet induced NAFLD through reshaping the gut microbiota to increase ursodeoxycholic acid (UDCA) level, thereby inhibiting farnesoid X receptor (FXR) accompanied with activated autophagy. Specifically, using dirty cage experiments and 16S rRNA sequencing, it identified that metformin could reshape microbiota to release liver injury as confirmed by the results of histopathology and biochemical index detection. Furthermore, the bile acids were found to be altered by metformin, in which, the UDCA, a FXR natural inhibitor, was observed a significantly increase. Meanwhile, the inhibited FXR and activated autophagy in metformin-treated mice were captured using western blot, qRT-PCR and immunofluorescence analysis. In addition, the benefit of UDCA against NAFLD was demonstrated in UDCA treated mice. Further investigation with FXR siRNA introduced to HepG2 cells revealed that inhibiting FXR can reduce oleic acids induced cell injury with the autophagy activation. In conclusion, this study highlights metformin's potential to ameliorate NAFLD by reshaping gut microbiota, thereby upregulating UDCA in the liver and restoring cholesterol synthesis capacity, possibly via inhibiting FXR to activate autophagy.
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Affiliation(s)
- Xiujie Liu
- Institute of microbiota and host inflammation-related diseases; School of Basic Medical Science, Wenzhou Medical University, Wenzhou 325035, China; Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo 315048, Zhejiang, China
| | - Hongxia Sun
- Institute of microbiota and host inflammation-related diseases; School of Basic Medical Science, Wenzhou Medical University, Wenzhou 325035, China
| | - Qiannian Han
- Institute of microbiota and host inflammation-related diseases; School of Basic Medical Science, Wenzhou Medical University, Wenzhou 325035, China
| | - Zekai Wang
- Institute of microbiota and host inflammation-related diseases; School of Basic Medical Science, Wenzhou Medical University, Wenzhou 325035, China
| | - Jingjing Zeng
- Institute of microbiota and host inflammation-related diseases; School of Basic Medical Science, Wenzhou Medical University, Wenzhou 325035, China
| | - Jianwei Liu
- Institute of microbiota and host inflammation-related diseases; School of Basic Medical Science, Wenzhou Medical University, Wenzhou 325035, China
| | - Shining Ou
- Institute of microbiota and host inflammation-related diseases; School of Basic Medical Science, Wenzhou Medical University, Wenzhou 325035, China
| | - Keke Jin
- Institute of microbiota and host inflammation-related diseases; School of Basic Medical Science, Wenzhou Medical University, Wenzhou 325035, China.
| | - Yuanyuan Shao
- Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo 315048, Zhejiang, China
| | - Dongbing Li
- Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo 315048, Zhejiang, China
| | - Zhuowei Gao
- Oncology Department, Shunde Hospital of Guangzhou University of Chinese Medicine, Guangdong 528300, China; Research Center of Translational Medicine, Shunde Hospital of Guangzhou University of Chinese Medicine, Guangdong 528300, China.
| | - Fangyan Wang
- Institute of microbiota and host inflammation-related diseases; School of Basic Medical Science, Wenzhou Medical University, Wenzhou 325035, China.
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Fulda ES, Portas L, Harper C, Preiss D, Bennett D, Doherty A. Association of Daily Steps with Incident Non-Alcoholic Fatty Liver Disease: Evidence from the UK Biobank Cohort. Med Sci Sports Exerc 2025:00005768-990000000-00789. [PMID: 40279651 PMCID: PMC7617666 DOI: 10.1249/mss.0000000000003738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/27/2025]
Abstract
PURPOSE Low physical activity has been shown to be associated with higher risk of non-alcoholic fatty liver disease (NAFLD). However, the strength and shape of this association are currently uncertain due to a reliance on self-reported physical activity measures. This report aims to investigate the relationship of median daily step count with NAFLD using accelerometer-derived step count from a large prospective cohort study. METHODS The wrist-worn accelerometer sub-study of the UK Biobank (N = ~100,000) was used to characterise median daily step count over a seven-day period. NAFLD cases were ascertained via record linkage with hospital inpatient data and death registers or by using a measure of liver fat from imaging. Cox proportional hazards models were employed to assess the association between step count and NAFLD, adjusting for age, sociodemographic, and lifestyle factors. Mediation analyses were conducted. RESULTS Among 91,031 participants (709,440 person-years of follow-up), there were 762 incident NAFLD cases. Higher step count was log-linearly and inversely associated with risk of NAFLD. A 1000-step increase (representing 10 minutes of walking) was associated with a 12% (95% CI: 10%-14%) lower hazard of NAFLD. When using imaging to identify NAFLD, a 1,000-step increase was associated with a 6% (95% CI: 6%-7%) lower risk. There was evidence for mediation by adiposity, accounting for 39% of the observed association. CONCLUSIONS Daily step count, a modifiable risk factor, is log-linearly and inversely associated with NAFLD. This association was only partially explained by adiposity. These findings from a large cohort study may have important implications for strategies to lower NAFLD risk.
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Affiliation(s)
- Evelynne S. Fulda
- Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
| | - Laura Portas
- Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
| | - Charlie Harper
- Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
| | - David Preiss
- Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
| | - Derrick Bennett
- Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
| | - Aiden Doherty
- Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, UNITED KINGDOM
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Mai X, Li M, Jin X, Huang S, Xu M, Yan B, Wei Y, Long X, Wu Y, Mo Z. Identification of a Risk-Prediction Model for Hypertension Patients Concomitant with Nonalcoholic Fatty Liver Disease. Healthcare (Basel) 2025; 13:969. [PMID: 40361747 PMCID: PMC12071756 DOI: 10.3390/healthcare13090969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/07/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
Objective: Our study aims to develop a personalized nomogram model for predicting the risk of nonalcoholic fatty liver disease (NAFLD) in hypertension (HTN) patients and further validate its effectiveness. Methods: A total of 1250 hypertensive (HTN) patients from Guangxi, China, were divided into a training group (875 patients, 70%) and a validation set (375 patients, 30%). LASSO regression, in combination with univariate and multivariate logistic regression analyses, was used to identify predictive factors associated with nonalcoholic fatty liver disease (NAFLD) in HTN patients within the training set. Subsequently, the performance of an NAFLD nomogram prediction model was evaluated in the separate validation group, including assessments of differentiation ability, calibration performance, and clinical applicability. This was carried out using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Results: The risk-prediction model for the HTN patients concomitant with NAFLD included oral antidiabetic drugs (OADs) (OR = 2.553, 95% CI: 1.368-4.763), antihypertensives (AHs) (OR = 7.303, 95% CI: 4.168-12.794), body mass index (BMI) (OR = 1.145, 95% CI: 1.084-1.209), blood urea nitrogen (BUN) (OR = 0.924, 95% CI: 0.860-0.992), triglycerides (TGs) (OR = 1.474, 95% CI: 1.201-1.809), aspartate aminotransferase (AST) (OR = 1.061, 95% CI: 1.018-1.105), and AST/ALT ratio (AAR) (OR = 0.249, 95% CI: 0.121-0.514) as significant predictors. The AUC of the NAFLD risk-prediction model in the training set and the validation set were 0.816 (95% CI: 0.785-0.847) and 0.794 (95% CI: 0.746-0.842), respectively. The Hosmer-Lemeshow test showed that the model has a good goodness-of-fit (p-values were 0.612 and 0.221). DCA suggested the net benefit of using a nomogram to predict the risk of HTN patients concomitant with NAFLD is higher. These results suggested that the model showed moderate predictive ability and good calibration. Conclusions: BMI, OADs, AHs, BUN, TGs, AST, and AAR were independent influencing factors of HTN combined with NAFLD, and the risk prediction model constructed based on this could help to identify the high-risk group of HTN combined with NAFLD at an early stage and guide the development of interventions. Larger cohorts with multiethnic populations are essential to verify our findings.
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Affiliation(s)
- Xiaoyou Mai
- School of Public Health, Guangxi Medical University, Nanning 530021, China; (X.M.); (Y.W.); (X.L.)
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, China; (M.L.); (X.J.); (S.H.); (M.X.); (B.Y.); (Y.W.)
| | - Mingli Li
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, China; (M.L.); (X.J.); (S.H.); (M.X.); (B.Y.); (Y.W.)
| | - Xihui Jin
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, China; (M.L.); (X.J.); (S.H.); (M.X.); (B.Y.); (Y.W.)
- Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning 530021, China
| | - Shengzhu Huang
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, China; (M.L.); (X.J.); (S.H.); (M.X.); (B.Y.); (Y.W.)
| | - Mingjie Xu
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, China; (M.L.); (X.J.); (S.H.); (M.X.); (B.Y.); (Y.W.)
- Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning 530021, China
| | - Boteng Yan
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, China; (M.L.); (X.J.); (S.H.); (M.X.); (B.Y.); (Y.W.)
- Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning 530021, China
| | - Yushuang Wei
- School of Public Health, Guangxi Medical University, Nanning 530021, China; (X.M.); (Y.W.); (X.L.)
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, China; (M.L.); (X.J.); (S.H.); (M.X.); (B.Y.); (Y.W.)
| | - Xinyang Long
- School of Public Health, Guangxi Medical University, Nanning 530021, China; (X.M.); (Y.W.); (X.L.)
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, China; (M.L.); (X.J.); (S.H.); (M.X.); (B.Y.); (Y.W.)
| | - Yongxian Wu
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, China; (M.L.); (X.J.); (S.H.); (M.X.); (B.Y.); (Y.W.)
- Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning 530021, China
| | - Zengnan Mo
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, China; (M.L.); (X.J.); (S.H.); (M.X.); (B.Y.); (Y.W.)
- Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning 530021, China
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Ruan S, Huang L, Song J, Yi Z, Sun W, Zhou F, Feng C, Du G, Xie J, Lu Y, Fan G. Global burden trends and forecasts for MAFLD in adolescents and young adults from 1990 to 2021. Sci Rep 2025; 15:13534. [PMID: 40253566 PMCID: PMC12009366 DOI: 10.1038/s41598-025-98489-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 04/11/2025] [Indexed: 04/21/2025] Open
Abstract
Metabolic-dysfunction associated fatty liver disease (MAFLD) is a widespread chronic liver condition that has been steadily increasing among adolescents and young adults in recent years, posing a major global public health concern. This study aims to conduct an in-depth analysis of the Global Burden of Disease (GBD) 2021 data on MAFLD, focusing on prevalence, incidence, and disability-adjusted life years (DALY) for individuals aged 15-39, spanning the period from 1990 to 2021. This research examines data from the GBD study covering 1990 to 2021 to assess the prevalence, incidence, and DALYs associated with of MAFLD in adolescents and young adults aged 15-39. The analysis is broken down by socioeconomic status, geographic regions, and specific countries. Advanced statistical methods, including the estimated annual percentage change (EAPC) and Bayesian age-period-cohort (BAPC) modeling, were used to deliver the most current and thorough epidemiological assessment of MAFLD in this demographic. In 2021, the estimated global cases of non-alcoholic fatty liver disease among adolescents and young adults reached approximately 423 million, representing a 75.31% increase from 1990. The age-standardized prevalence rate (ASPR) was 14,221.32 cases per 100,000 population, and the age-standardized incidence rate (ASIR) was 977.61 cases per 100,000 population in 2021. Between 1990 and 2021, the ASPR, ASIR, age-standardized DALY rate, and age-standardized mortality rate showed a continuous upward trend, with EAPC of 0.84, 0.79, 0.65, and 0.81, respectively. Regions with Middle and Low-middle Socio-Demographic Index (SDI), as well as High-middle SDI, emerged as "hotspots" for MAFLD prevalence, particularly in North Africa, the Middle East, East Asia, and South Asia. Males exhibited higher prevalence rates compared to females, and the rates continued to increase across all adolescents and young adult age groups. By 2050, the ASPR for MAFLD among this population is projected to reach 16,101 cases per 100,000, signaling an alarming trend. Over the last 30 years, the burden of metabolic-dysfunction associated fatty liver disease has significantly increased among adolescents and young adults worldwide. To counter this rising global health concern, it is crucial to develop and implement targeted and effective interventions tailored to socio-economic settings.
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Affiliation(s)
- Shiying Ruan
- Jiangxi Provincial Key Laboratory of Prevention and Treatment of Infectious Diseases, Jiangxi Medical Center for Critical Public Health Events, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330052, People's Republic of China
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, Jiangxi, 330047, People's Republic of China
| | - Liyuan Huang
- Department of Occupational Health and Toxicology, School of Public Health, Nanchang University, Nanchang, 330006, People's Republic of China
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Jie Song
- Jiangxi Province Healthcare Security Monitoring Center, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Zusong Yi
- Jiangxi Province Healthcare Security Monitoring Center, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Weipeng Sun
- Department of Occupational Health and Toxicology, School of Public Health, Nanchang University, Nanchang, 330006, People's Republic of China
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Fankun Zhou
- Department of Occupational Health and Toxicology, School of Public Health, Nanchang University, Nanchang, 330006, People's Republic of China
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Chang Feng
- Department of Occupational Health and Toxicology, School of Public Health, Nanchang University, Nanchang, 330006, People's Republic of China
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Guihua Du
- Department of Occupational Health and Toxicology, School of Public Health, Nanchang University, Nanchang, 330006, People's Republic of China
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Jie Xie
- Department of Occupational Health and Toxicology, School of Public Health, Nanchang University, Nanchang, 330006, People's Republic of China
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Yuanan Lu
- Department of Public Health Sciences, University of Hawaii at Manoa, Honolulu, HI, 96822, USA.
- Environmental Health Laboratory, Department of Public Health Sciences, University of Hawaii, Honolulu, HI, 96822, USA.
| | - Guangqin Fan
- Department of Occupational Health and Toxicology, School of Public Health, Nanchang University, Nanchang, 330006, People's Republic of China.
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, 330006, Jiangxi, People's Republic of China.
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Feng X, Song X, Yang X, Luan F, Gu Y, Zheng F, Guo H, Qiao S. MAFLD mediates the association between CHR and gallstones in the U.S. adults: evidence from NHANES 2021-2023. BMC Gastroenterol 2025; 25:268. [PMID: 40247188 PMCID: PMC12007222 DOI: 10.1186/s12876-025-03805-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/19/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Gallstones, a global hepatobiliary disorder, are linked to systemic inflammation, lipid disturbances, and metabolic-associated fatty liver disease (MAFLD). This population-based study aims to investigate the association of the novel inflammation-lipid composite biomarker high-sensitivity C-reactive protein-to-HDL cholesterol ratio (CHR) with gallstones and evaluate whether MAFLD mediates this relationship. METHODS This cross-sectional analysis utilized data from the National Health and Nutrition Examination Survey (NHANES, 2021-2023) to assess the correlation between the CHR and gallstone prevalence through weighted logistic regression. To evaluate potential nonlinear relationships and assess heterogeneity across key demographics, restricted cubic splines (RCS) were employed to model the association, complemented by subgroup analyses stratified by age, sex, and other covariates. A mediation analysis was used for elucidating the mediating effects of MAFLD. RESULTS Among 4,078 participants, 432 (10.60%) had gallstones. After adjusting for confounders, each unit increase in CHR was associated with a 165% increased risk of gallstones (OR: 2.65, 95% CI: 1.43-4.93, P = 0.006). The RCS curve demonstrated a nonlinear association between the CHR and gallstones (Poverall < 0.001, Pnonlinear < 0.001). Mediation analysis indicated that MAFLD explained 27.1% of this association. CONCLUSIONS CHR is positively associated with gallstones, with MAFLD partially mediating this relationship. Managing CHR levels and preventing MAFLD may reduce gallstone incidence.
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Affiliation(s)
- Xin Feng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Xiangyu Song
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Xi'an Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Fuxiang Luan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yufei Gu
- Department of General Surgery, The First Affiliated Hospital of Henan University, Kaifeng, Henan, 475001, China
| | - Fengyu Zheng
- Department of Comprehensive Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, 710068, China
| | - Huahu Guo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Shishi Qiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
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McPherson S, Abbas N, Allison MED, Backhouse D, Boothman H, Cooksley T, Corless L, Crame T, Cross TJS, Henry J, Hogan B, Mansour D, McGinty G, McKinnon G, Patel J, Tavabie OD, Williams F, Hollywood C. Decompensated cirrhosis: an update of the BSG/BASL admission care bundle. Frontline Gastroenterol 2025:flgastro-2025-103074. [DOI: 10.1136/flgastro-2025-103074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/03/2025] Open
Abstract
Acute decompensated cirrhosis (DC) and acute-on-chronic liver failure are common reasons for hospital admission that have a high in-hospital mortality rate (10%–20%). Patients require a detailed assessment for precipitating factors and management of complications such as infections, ascites, acute kidney injury and hepatic encephalopathy. Multiple reports have demonstrated unwarranted variability in the care of patients with DC. In 2014, the British Society of Gastroenterology (BSG)/British Association for the Study of the Liver (BASL) DC care bundle (DCCB) was introduced to provide a structured approach for the management of patients with DC in the first 24 hours. Usage of the DCCB has been shown to improve care of patients with DC. However, despite evidence indicating the beneficial impact of the DCCB, overall usage across the UK was only 11.4% in a national audit. Our aim was to update the DCCB to incorporate recent advances in care and improve its usability and develop a strategy to improve its usage nationally. The updated bundle was developed by a multidisciplinary group of specialists from BSG, BASL and the Society for Acute Medicine with the quality of evidence supporting the bundle recommendations assessed using the Grading of Recommendation Assessment Development and Evaluation tool. Proposed minimum standards for audit were also developed. Finally, a strategy to promote usage of the bundle including education/training at a national and local level, improving accessibility for the bundle, and promotion of frameworks for use at an institutional level to improve and monitor utilisation of DCCB.
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Zhang XL, Gu Y, Zhao J, Zhu PW, Chen WY, Li G, Liu WY, Zheng W, Zhang N, Chen LL, Targher G, Byrne CD, Niu K, Sun DQ, Zheng MH. Associations between skeletal muscle strength and chronic kidney disease in patients with MASLD. COMMUNICATIONS MEDICINE 2025; 5:118. [PMID: 40240577 PMCID: PMC12003656 DOI: 10.1038/s43856-025-00821-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND A skeletal muscle strength (SMS) decline is associated with metabolic diseases, but whether SMS also declines with chronic kidney disease (CKD) in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) is uncertain. This study examined the associations between SMS and the risk of CKD in MASLD population. METHOD We performed a large-scale study with four cohorts: PERSONS and NHANES 2011-2014 cohorts for the cross-sectional investigation, and TCLSIH and UK Biobank cohorts for the longitudinal investigation. A handgrip dynamometer measured handgrip strength as a proxy for overall SMS. Participants were stratified according to CKD status [non-CKD vs. CKD (stages 1-5) groups]. RESULTS In the PERSONS cohort, the CKD group has a lower handgrip strength than the non-CKD group (27.14 ± 9.19 vs. 33.59 ± 11.92 kg, P < 0.001). Higher handgrip strength is associated with lower odds of abnormal albuminuria or CKD (OR: 0.96, 95%CI:0.92-0.99 and OR:0.95, 95%CI: 0.91-0.99 respectively). The highest handgrip strength tertile is associated with the lowest risk of having abnormal albuminuria or CKD (compared with the lowest or middle tertile). Results are similar in NHANES cohort. Furthermore, the highest handgrip strength is independently associated with the lowest risk of incident CKD in MASLD (HR: 0.95, 95%CI: 0.92-0.99 and HR:0.99, 95%CI: 0.98-0.99 in TCLSIH and UK Biobank cohorts). In Kaplan-Meier curve analysis, the cumulative incidence of CKD is lowest in the highest handgrip strength tertile compared to the lowest or the middle tertile. CONCLUSIONS Higher handgrip/muscle strength is independently associated with a lower risk of CKD and abnormal albuminuria in MASLD population.
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Affiliation(s)
- Xin-Lei Zhang
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Yeqing Gu
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jing Zhao
- Urologic Nephrology Center, Jiangnan University Medical Center, Wuxi, China
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China
| | - Pei-Wu Zhu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wen-Ying Chen
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Li
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Infectious, Jining No.1 People's Hospital, Jining, China
| | - Wen-Yue Liu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wen Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ni Zhang
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Li-Li Chen
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy
- Metabolic Diseases Research Unit, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health and Care Research, Biomedical Research Centre, University Hospital Southampton and University of Southampton, Southampton General Hospital, Southampton, UK
| | - Kaijun Niu
- School of Public Health of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China.
| | - Dan-Qin Sun
- Urologic Nephrology Center, Jiangnan University Medical Center, Wuxi, China.
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China.
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
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Liu H, Yang Z, Li J, Zhang J, Sun C. Expanding the horizons of bicyclol in multiple diseases: Mechanisms, therapeutic implications and challenges. Eur J Pharmacol 2025; 993:177381. [PMID: 39954842 DOI: 10.1016/j.ejphar.2025.177381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/25/2025] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Bicyclol, a drug stemmed from the traditional Chinese medicine Schisandra chinensis, has been widely utilized in clinical practice due to its efficacy and safety to manage hepatopathy. Its diverse biological properties-including antiviral, anti-inflammatory, antifibrotic, immunomodulatory, antioxidative, antisteatotic, and antitumor effects-underscore its significant medicinal effects in versatile hepatic disorders, incorporating viral hepatitis, non-alcoholic fatty liver disease, hepatocellular carcinoma, acute hepatic failure, hepatic fibrosis as well as drug-induced liver injury. Furthermore, ongoing researches into the molecular mechanisms, biological activities and mode of actions concerning bicyclol have uncovered its potential therapeutic implications in other multiple diseases/conditions. Studies have indicated promising efficacy pertaining to bicyclol to treat idiopathic pulmonary fibrosis, acute lung injury, cerebral ischemia/reperfusion injury, renal dysfunction, renal cell carcinoma, and cardiovascular diseases. Accordingly, this narrative review article summarizes the current understanding of diverse biological activities and underpinning mechanisms of bicyclol across a range of diseases, as well as its pharmacokinetics, toxicity profile and shed light on future perspectives.
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Affiliation(s)
- Heng Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin, 300308, China
| | - Ziyi Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, China
| | - Jia Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, China.
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin, 300308, China.
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Pădureanu V, Dop D, Radu L, Rădulescu D, Pădureanu R, Pîrșcoveanu DFV, Caragea DC. Nephrological, Pulmonary, and Dermatological Complications in the Context of MAFLD/NAFLD: A Narrative Review. Metabolites 2025; 15:272. [PMID: 40278401 PMCID: PMC12029749 DOI: 10.3390/metabo15040272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/07/2025] [Accepted: 04/11/2025] [Indexed: 04/26/2025] Open
Abstract
Background: The most common cause of chronic liver disease is now known to be non-alcoholic fatty liver disease (NAFLD), recently redefined as metabolic-associated fatty liver disease (MAFLD). This review aims to synthesize current evidence on the pathophysiology and clinical implications of nephrological, pulmonary, and dermatological manifestations among NAFLD/MAFLD patients. In order to find safe and efficient treatments, NAFLD/MAFLD has emerged as a primary concern for hepatologists worldwide. Methods: We conducted a comprehensive review of the literature from major databases, focusing on studies that evaluated the extrahepatic manifestations of NAFLD/MAFLD. Emphasis was placed on identifying pathophysiological mechanisms and assessing their clinical impact on renal, pulmonary, and dermatological systems. Results: Recent developments in the management of chronic viral hepatitis have lowered the mortality rate associated with chronic liver disease. However, the prevalence of NAFLD/MAFLD continues to rise, making chronic liver disease a significant health concern for the future. An increasing percentage of patients on liver transplant waiting lists now have cirrhosis and hepatocellular carcinoma due to non-alcoholic liver disease. Furthermore, the incidence and prevalence of chronic kidney disease have surged, linking NAFLD/MAFLD to higher morbidity, mortality, and healthcare costs. Conclusions: NAFLD/MAFLD is underdiagnosed and underappreciated, yet its incidence is rapidly increasing, raising concerns about a potential global epidemic. Given its multisystemic impact-extending to renal, pulmonary, and dermatological complications-it is crucial to develop interdisciplinary strategies for early detection and effective management of the disease.
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Affiliation(s)
- Vlad Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
| | - Dalia Dop
- Department of Pediatrics, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
| | - Lucrețiu Radu
- Department of Hygiene, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
| | - Dumitru Rădulescu
- Department of Surgery, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
| | - Rodica Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
| | | | - Daniel Cosmin Caragea
- Department of Nephrology, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania;
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Zhang Z, Zheng Q, Liu Y, Chen G, Li Y. Association between periodontitis and mortality in participants with metabolic dysfunction-associated steatotic liver disease: results from NHANES. BMC Oral Health 2025; 25:567. [PMID: 40223086 PMCID: PMC11995466 DOI: 10.1186/s12903-025-05959-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 04/04/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND It has been reported that periodontitis was a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this study is to investigate the impact of periodontitis on all-cause and cause-specific mortality of MASLD patients. METHODS We included 11,019 individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) from the National Health and Nutrition Examination Survey. Multivariable Cox proportional hazards models were utilized to analyze the estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality and cause-specific mortality among participants with different periods of periodontitis status. Additionally, we employed restricted cubic splines (RCS) curves to explore the dose-response relationship between clinical attachment level (CAL) and pocket probing depth (PPD) and mortality rates. Finally, a series of sensitivity analyses and stratification analyses were conducted to test the reliability and robustness of the results. RESULTS In this study, moderate to severe periodontitis significantly increased the all-cause mortality (HR 1.29, 95% CI 1.08-1.55; P = 0.003) and cardiovascular disease (CVD)-related mortality (HR 1.41, 95% CI 1.10-1.79; P = 0.006) among MASLD participants. However, no significant effects of different periodontal statuses on cancer mortality were observed among MASLD participants. CONCLUSIONS A nationwide large-sample longitudinal study indicated that MASLD patients with moderate to severe periodontitis experienced significantly higher all-cause and CVD-related mortality rates compared to those with no or mild periodontitis.
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Affiliation(s)
- Zhaofu Zhang
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, PR China
| | - Qiuyun Zheng
- Department of Obstetrics and Gynecology, Zigui County People's Hospital, Zigui, 443200, PR China
| | - Yiheng Liu
- School of Medicine, Sun Yat-sen University, Shenzhen, 518107, PR China
| | - Guanhui Chen
- Department of Stomatology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, PR China.
| | - Yiming Li
- Department of Stomatology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, PR China.
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Liu J, Zhou Y, Li Y, Chen Z, Jiao X, Hu J, Wei Q, Mi Y, Li P. Integrative transcriptomic and metabolomic analysis explores the mechanisms by which ACT001 treats MAFLD in mice. Sci Rep 2025; 15:12494. [PMID: 40216908 PMCID: PMC11992053 DOI: 10.1038/s41598-025-97312-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 04/03/2025] [Indexed: 04/14/2025] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) represents a significant public health concern. Previous studies have shown that ACT001 has therapeutic effects on MAFLD. This study investigated the potential mechanisms by which ACT001 may treat MAFLD through an integrated approach of transcriptomics and metabolomics. MAFLD model induced by high-fat diet was established, and ACT001 was given by gavage. Histological analysis was performed, and liver enzyme and lipid levels were measured. Transcriptomic analysis was performed to identify differentially expressed genes, while metabolomic analysis was used to detect differential metabolites. Pathways enriched by genes and metabolites affected by ACT001 were also identified. The differentially expressed genes were confirmed through RT-qPCR. ACT001 reduced the levels of liver enzymes and lipids, and alleviated pathological damage such as hepatic steatosis. The integration of transcriptomic and metabolomic analyses indicated that ACT001 may alleviate high-fat diet-induced MAFLD by regulating the linoleic acid and glutathione metabolic pathways. The validation of five differentially expressed genes using RT-qPCR yielded results that were consistent with the transcriptomics data. ACT001 may exert a therapeutic effect in MAFLD mice by modulating glutathione metabolism and linoleic acid metabolism. It has the potential to be a promising treatment for MAFLD.
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Affiliation(s)
- Jing Liu
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, 300192, China
| | - Yibing Zhou
- Central Laboratory, Department of Scientific Research, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Jiangsu, China
| | - Yinglun Li
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, 300192, China
| | - Ze Chen
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, 300192, China
| | - Xue Jiao
- Clinical School of the Second People's Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jingqin Hu
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, 300192, China
| | - Qian Wei
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, 300192, China
| | - Yuqiang Mi
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, 300192, China
- Tianjin Research Institute of Liver Diseases, Tianjin, China
| | - Ping Li
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, 300192, China.
- Tianjin Research Institute of Liver Diseases, Tianjin, China.
- Tianjin Integrated Traditional Chinese and Western Medicine Institute of Infectious Diseases, Tianjin, China.
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