Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global pandemic and the most critical implication for liver transplantation. In the present study, we investigated the role of CC motif chemokine ligand 7 (CCL7) in MASLD pathogenesis focusing on mechanism and translational potential. We report that CCL7 blockade with a neutralization antibody attenuated MASLD in mice. RNA-seq performed in hepatocytes identified hypermethylated in cancer 1 (HIC1) as a novel target gene responsive to CCL7 treatment. CCL7 induced HIC1 expression was mediated by steroid receptor co-activator 1 (SRC-1) in a redox-sensitive manner. Mechanistically, enhanced ROS production by CCL7 activated protein kinase C theta (PKCθ), which in turn phosphorylated SRC-1 thereby enabling SRC-1 recruitment to the Hic1 promoter. Consistently SRC-1 depletion or HIC1 depletion ameliorated MASLD in mice. Further analysis revealed that SRC-1 activated Hic1 transcription in part by recruiting protein arginine methyltransferase 4 (PRMT4) in a redox-sensitive and phosphorylation-dependent manner. Importantly, pharmaceutical inhibition of PRMT4 activity with a small-molecule compound TP-064 mitigated MASLD in mice. Finally, relevance of the CCL7-SRC-1-PRMT4-HIC1 axis was confirmed in MASLD patients. In conclusion, our data uncover a previously unrecognized redox-sensitive mechanism underlying MASLD pathogenesis and present druggable targets for MASLD intervention.

Metabolic dysfunction - Associated Steatotic Liver Disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), poses a significant clinical burden due to its high prevalence and potential progression to fibrosis. While neutrophil extracellular traps (NETs) have been implicated in MASLD progression, their specific role in fibrosis remains unclear. This study integrates transcriptomic and single-cell data using weighted gene co-expression network analysis (WGCNA), causal WGCNA (CWGCNA), single-sample gene set enrichment analysis (ssGSEA), gene set variation analysis (GSVA), and linear models for microarray data (Limma) to identify key genes driving steatosis-to-fibrosis transition. Validation in human serum, mouse liver tissue, and mouse serum confirmed that SERPINE1 and THBS1 as robust non-invasive biomarkers with strong diagnostic performance. When combined with clinical features, these markers improved fibrosis prediction accuracy in MASLD patients. Additionally, SERPINE1 appears to mediate interactions between hepatic stellate cells and neutrophils, highlighting a novel therapeutic target. Overall, our findings reveal that NETs-related genes, particularly SERPINE1 and THBS1, hold strong diagnostic value for early-stage fibrosis in MASLD. Targeting SERPINE1 in hepatic stellate cells offers a promising strategy for therapeutic intervention. This study provides a novel framework for non-invasive MASLD fibrosis prediction and lays the foundation for targeted interventions to mitigate disease progression.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder globally. The prevalence of NAFLD in the general population is estimated to be 25-30 %, making it the most common chronic liver condition in China as well as worldwide. Given the escalating disease burden and the scarcity of effective therapeutic interventions, there is a pressing unmet clinical need. Consequently, the development of novel pharmaceuticals has emerged as a pivotal research focus in recent years. Moreover, the advent of nano-delivery technology offers innovative solutions for NAFLD drug therapy. This paper presents a comprehensive examination of the pathogenesis and therapeutic targets of NAFLD. It critically reviews the latest advancements in nanomedicine research pertinent to NAFLD treatment. The review synthesizes a broad range of research findings to bridge the gap between current knowledge and emerging therapeutic strategies, and aims to inform and guide future research directions in NAFLD management.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading chronic liver disease characterized by chronic inflammation. Regulatory T cells (Tregs) highly express CD73 and play a critical role in modulating the immune response. However, the roles and mechanisms by which CD73 modulates Tregs in MASLD are still unknown. A choline-deficient high-fat diet (CDHFD) or methionine/choline-deficient diet (MCD) was used to establish a MASLD model. We found that CD73 expression was upregulated in Tregs via the FFA-mediated p38/GATA2 signaling pathway. Cd73 KO promoted MASLD progression, accompanied by decreased Treg viability and activity. Compared with Cd73 KO Tregs, adoptively transferred WT Tregs exhibited increased Treg activity and provided greater protection against hepatic inflammatory responses in MASLD. This immune protection is mediated by CD73 via both enzymatic and nonenzymatic pathways, degrading AMP into ADO to increase Treg function and block DR5-TRAIL-mediated cell death signaling. These findings suggest a potential immunotherapeutic approach for MASLD treatment and highlight its possible relevance for clinical application.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a spectrum of liver damage starting with liver steatosis and lipid disorders presented as the hallmark. Cannabinoid-2 receptor (CB2R) is the receptor of endocannabinoids mainly expressed in immune cells. Our preliminary study revealed the preventative role of CB2R in liver injury related to lipid metabolism. In this study, we aimed to explore the role of CB2R in NAFLD and the underlying mechanism related to microbial community. High-fat diet-induced NAFLD model was established in mice. We found that hepatic CB2R expression was significantly reduced in NAFLD mice and CB2R-/- mice fed with normal chow. Interestingly, cohousing with or transplanted with microbiota from WT mice, or treatment with an antibiotic cocktail ameliorated the NAFLD phenotype of CB2R-/- mice. The gut dysbiosis in CB2R-/- mice including increased Actinobacteriota and decreased Bacteroidota was similar to that of NAFLD patients and NAFLD mice. Microbial functional analysis and metabolomics profiling revealed obviously disturbed tryptophan metabolism in NAFLD patients and NAFLD mice, which were also seen in CB2R-/- mice. Correlation network showed that the disordered tryptophan metabolites such as indolelactic acid (ILA) and xanthurenic acid in CB2R-/- mice were mediated by gut dysbiosis and related to NAFLD severity indicators. In vitro and in vivo validation experiments showed that the enriched tryptophan metabolites ILA aggravated NAFLD phenotypes. These results demonstrate the involvement of CB2R in NAFLD, which is related to gut microbiota-mediated tryptophan metabolites. Our findings highlight CB2R and the associated microbes and tryptophan metabolites as promising targets for the treatment of NAFLD.

The Glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) are well-established drug targets for the treatment of diabetes and obesity. Studies have linked GLP-1R agonist to cardiometabolic diseases (CMDs), while the therapeutic potential of the GIPR agonist remains a topic of debate.

Using genetic variants as instrumental variables, we performed a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between genetically proxied GIPR agonist and 23 CMD outcomes, and a two-step mediation analysis to identify mediating inflammatory biomarkers. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by sensitivity analyses to validate robustness.

The genetic mimicry of GIPR enhancement showed significant protective associations with 14 CMDs. Mediation analysis revealed that Fms-related tyrosine kinase 3 ligand (Flt3L) partially mediated the effects of GIPR agonist on angina (OR 0.997 [0.995-0.999], P = 0.0048) and myocardial infarction(MI) (OR 0.998 [0.996-0.999], P = 0.0077), accounting for 15.49% and 16.71% of the total risk reduction, respectively.

Our study revealed that GIPR agonist lowers the risk of 14 CMDs. Flt3L is pinpointed as a key mediating factor in reducing angina and MI risk, suggesting a new therapeutic avenue.

Metabolic dysfunction-associated steatohepatitis (MASH), the progressed period of metabolic dysfunction-associated steatotic liver disease (MASLD), is a multifaceted liver disease characterised by inflammation and fibrosis that develops from simple steatosis, even contributing to hepatocellular carcinoma and death. MASH involves several immune cell-mediated inflammation and fibrosis, where T cells play a crucial role through the release of pro-inflammatory cytokines and pro-fibrotic factors. This review discusses the complex role of various T cell subsets in the pathogenesis of MASH and highlights the progress of ongoing clinical trials involving T cell-targeted MASH therapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common feature of obesity and type 2 diabetes. Under lipotoxic stress, hepatocytes release small extracellular vesicles (sEVs) which act locally and contribute to MASLD progression, but their role in beta cell function and development of type 2 diabetes remains largely unexplored. We aimed to examine whether hepatocyte-derived sEVs (Hep-sEVs) under lipotoxic conditions impact on liver and pancreas inflammation and subsequent effects on beta cell function.

Primary mouse hepatocytes and Huh7 human hepatocytes were treated with palmitic acid and Hep-sEVs were purified from the culture medium by differential ultracentrifugation. In vitro and in vivo approaches were used to decipher the role of Hep-sEVs in liver and pancreas inflammation and beta cell dysfunction in mouse and human pancreatic islets. The contribution of the Toll-like receptor 4 (TLR4) to Hep-sEV-mediated effects was investigated in pancreatic islets from myeloid-specific TLR4-deficient mice.

Lipotoxic Hep-sEVs targeted pancreatic islet macrophages and induced TLR4-mediated inflammation. The subsequent inflammatory response downregulated beta cell identity genes and impaired glucose-stimulated insulin secretion in both INS-1 beta cells (p<0.05) and isolated pancreatic islets from mice (p<0.01) and humans (p<0.05). Specific deletion of TLR4 in macrophages protected pancreatic islets against inflammation and the impairment of glucose-stimulated insulin secretion induced by lipotoxic Hep-sEVs. Chronic administration of lipotoxic Hep-sEVs in lean mice induced liver and pancreas inflammation through the recruitment of immune cells. This intervention induced hepatocyte injury and fibrotic damage together with detrimental immunometabolic systemic effects. Insulin resistance in hepatocytes (p<0.01) and a compensatory insulin secretion (p<0.001) that prevented glucose intolerance were also observed in mice treated with lipotoxic Hep-sEVs.

This study has provided evidence of liver and pancreas inflammation and beta cell dysfunction induced by lipotoxic Hep-sEVs. Our data also envision TLR4-mediated signalling in islet macrophages as a key mediator of the effects of lipotoxic Hep-sEVs on beta cell function.

The rising incidence of nonalcoholic fatty liver disease (NAFLD) poses a great socioeconomic burden worldwide. Also, periodontitis is the most common chronic inflammatory disease caused by a group of oral pathogens, affecting both oral health and systemic conditions, especially liver disease. Although accumulating evidence has elucidated an association between periodontal pathogens and NAFLD, the role of periodontal pathogen-derived outer membrane vesicles (OMVs) has not yet been clarified. In this comprehensive review, we aim to address this gap by summarising the progression and pathogenesis of NAFLD and revealing the relationship between periodontal disease and NAFLD multidimensionally. Additionally, this review sheds light on the multifunctional roles of periodontal pathogens OMVs and emphasises that periodontal pathogen-derived OMVs promote the development of NAFLD by stimulating Kupffer cells to produce inflammatory factors and inducing the activation of Hepatic stellate cells. However, it is still controversial whether periodontal pathogen-derived OMVs can be transferred to the liver through the bloodstream route or the oral-gut-liver axis. This highlights the pressing need for continued research efforts to develop new and optimised research schemes to observe the formation of the systemic distribution pathway of periodontal pathogen-derived OMVs. Finally, it is notable that there are currently no relevant clinical treatment guidelines to make specific provisions on controlling the level of periodontal pathogen-derived OMVs in patients with NAFLD. Guidelines developed based on our findings may contribute to the standardisation of practices. It can also provide effective strategies and potential therapeutic targets for NAFLD patients with periodontitis to alleviate the development of NAFLD diseases by inhibiting periodontal pathogens OMVs.

To examine the relationship between biological aging and the prevalence of NAFLD.

We used the recommended sampling weights to account for the complex survey design of NHANES. The analysis, utilizing data from 2005 to 2016, aimed to investigate the impact of biological aging on NAFLD prevalence using various statistical methods. A restricted cubic spline (RCS) model was applied to explore the dose-response relationship, while logistic regression examined linear associations. The robustness of the association across different subgroups was also tested.

The study included 2786 participants. We found significant associations between NAFLD and the following biological aging metrics: AL score (OR (95%CI) = 1.1932 (1.0597 ~ 1.3435), P = 0.0035), HD (OR (95%CI) = 1.2092 (1.0565 ~ 1.3839), P = 0.0058), and PA (OR (95%CI) = 1.7564 (1.1949 ~ 2.5818), P = 0.0042). All biological aging metrics were identified as independent predictors. PA was most associated with the prevalence of NAFLD. The associations persisted across most subgroups.

The prevalence of NAFLD was associated with biological aging, emphasizing the importance of addressing potential health risks related to aging.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing public health burden with limited therapeutic options. Recent studies have revealed that fibroblast growth factor 21 (FGF21)-based analogs can significantly improve MASH, but the mechanisms for this effect are not well understood. Here, we demonstrate that the beneficial metabolic effects of FGF21 to reverse MASH are mediated through distinct mechanisms to independently lower hepatic triglyceride and cholesterol levels. Specifically, FGF21 signaling directly to glutamatergic neurons in the central nervous system (CNS) stimulates hepatic triglyceride reduction and reversal of fibrosis, whereas FGF21 signaling directly to hepatocytes is necessary and sufficient to reduce hepatic cholesterol levels in mice. Mechanistically, we show that FGF21 acts in the CNS to increase sympathetic nerve activity to the liver, which suppresses hepatic de novo lipogenesis. These results provide critical insights into a promising pharmacological target to treat MASH.

Metabolic dysfunction-associated steatohepatitis (MASH) is becoming increasingly prevalent. Regulated cell death (RCD) has emerged as a significant disease phenotype and may act as a marker for liver fibrosis. The present study aimed to investigate the regulation of RCD-related genes in MASH to elucidate the role of RCD in the progression of MASH.

The gene expression profiles from the GSE130970 and GSE49541 datasets were retrieved from the Gene Expression Omnibus (GEO) database for analysis. A total of 101 combinations of 10 machine learning algorithms were employed to screen for characteristic RCD-related differentially expressed genes (DEGs) that reflect the progression of MASH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to explore the enrichment pathways and functions of the feature genes. we performed cell classification analysis to investigate immune cell infiltration. Consensus cluster analysis was performed to identify MASH subtypes associated with RCD. The GSE89632 dataset was utilized to analyze the correlation of characteristic genes with clinical features of MASH. The DGIdb database was employed to screen for potential therapeutic drugs and compounds targeting the feature genes. In addition, we established mouse liver fibrosis models induced by methionine-choline-deficient (MCD) diet or CCl4 treatment, and further validated the expression of characteristic genes through quantitative real-time PCR (q-PCR). Lastly, we knocked down EPHA3 in LX2 cells to explore its effect on TGFb-induced activation of LX2 cells.

This study discovered a total of 11 RCD-associated DEGs, which predicted the progression of MASH. Advanced MASH has higher levels of immune cell infiltration and is significantly correlated with the RCD-related DEGs expression. MASH can be classified into two subtypes, cluster 1 and cluster 2, based on these feature genes. Compared with cluster 1, cluster 2 has highly expressed RCD-related DEGs, shows an increase in the degree of fibrosis. Furthermore, We discovered that the expression levels of feature genes were positively correlated with AST and ALT levels. Subsequently, We also evaluated the expression of these 11 feature genes in the liver tissues of mice with fibrosis induced by MCD or CCl4, and the results suggested that these genes may be involved in the development of fibrosis. WB results showed that the protein level of EPHA3 significantly increased in both mouse models of liver fibrosis. In vitro, we observed that knocking down EPHA3 in LX2 cells significantly inhibited the activation of the TGF-β/Smad3 signaling pathway.

Our study sheds light on the fact that RCD contribute to the progression of MASH, high lighting potential therapeutic targets for treating this disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic inflammatory disorder characterized by alcohol-independent hepatic lipid accumulation, remains poorly understood in terms of PANoptosis involvement.

We integrated high-throughput sequencing data with bioinformatics to profile differentially expressed genes (DEGs) and immune infiltration patterns in MASLD, identifying PANoptosis-associated DEGs (PANoDEGs). Machine learning algorithms prioritized key PANoDEGs, while ROC curves assessed their diagnostic efficacy. Cellular, animal, and clinical validations confirmed target expression.

Three PANoDEGs (SNHG16, Caspase-6, and Dynamin-1-like protein) exhibited strong MASLD associations and diagnostic significance. Immune profiling revealed elevated M1 macrophages, naïve B cells, and activated natural killer cells in MASLD tissues versus controls. Further experiments verified the expression of the key PANoDEGs.

This study provides new insights for further studies on the pathogenesis and treatment strategies of PANoptosis in MASLD.

Non-alcoholic steatohepatitis (NASH) has emerged as a prevalent chronic liver disease with a huge unmet clinical need. A few studies have reported the beneficial effects of Poria cocos Wolf (P. cocos) extract on NASH mice, but the active components were still unknown. In this study we investigated the therapeutic effects of dehydrotrametenolic acid methyl ester (ZQS5029-1), a lanosterol-7,9(11)-diene triterpenes in P. cocos, in a high-fat diet plus CCl4 induced murine NASH model and a GAN diet induced ob/ob murine NASH model. The NASH mice were treated with ZQS5029-1 (75 mg·kg-1·d-1, i.g.) for 6 and 8 weeks, respectively. We showed that ZQS5029-1 treatment markedly relieved liver injury, inflammation and fibrosis in both the murine NASH models. We found that ZQS5029-1 treatment significantly suppressed hepatic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in both the NASH murine models, and blocked lipopolysaccharides (LPS)+adenosine 5'-triphosphate (ATP)/Nigericin-induced NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs) and Kupffer cells in vitro. We demonstrated that ZQS5029-1 directly bound to the H236 residue of mouse Caspase-1, thereby inhibiting NLRP3 inflammasome activation. The effects of ZQS5029-1 on macrophage-hepatocyte/HSC crosstalk were analyzed using the supernatants from macrophages preconditioned with LPS + ATP introduced into hepatocytes and hepatic stellate cells (HSCs). We found that the conditioned medium from the BMDMs induced injury and death, as well as lipid accumulation in hepatocytes, and activation of HSCs; these effects were blocked by conditioned medium from BMDMs treated with ZQS5029-1. Moreover, the protective effects of ZQS5029-1 on hepatocytes and HSCs were eliminated by H236A-mutation of Caspase-1. We conclude that ZQS5029-1 is a promising lead compound for the treatment of NASH by inhibiting NLRP3 inflammasome activation through targeting Caspase-1 and regulating the macrophage-hepatocyte/HSC crosstalk.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic condition with an incompletely understood pathogenesis. In this study, five candidate genes-RAG1, CKAP2, CENPK, TYMS, and BUB1-were identified as being associated with NAFLD progression through integrative bioinformatics analyses. A predictive model incorporating these genes demonstrated strong robustness and diagnostic accuracy. Single-nucleus RNA sequencing analysis further revealed that RAG1 plays a potential role in hepatocytes of NAFLD patients. Functional experiments using RNA interference to suppress RAG1 expression in HepG2 cells treated with oleic and palmitic acids showed reduced total glyceride and cholesterol levels, mitigated lipid accumulation, and alterations in pathways related to lipid metabolism, inflammation, and fibrosis. Furthermore, adeno-associated virus-specific knockdown of RAG1 in hepatocytes attenuated hepatic steatosis in high-fat diet-fed mice. These findings suggest that investigating the molecular mechanisms of hub genes like RAG1 may advance our understanding of NAFLD pathogenesis and inform therapeutic development.

Metabolic dysfunction-associated steatotic liver disease (MASLD) progresses to metabolic dysfunction-associated steatohepatitis (MASH) and is a major cause of liver cirrhosis. Although liver inflammation is the hallmark feature of MASH versus MASLD, the involvement of the peripheral immune cell compartments in disease progression is poorly understood, and single-cell profiles of peripheral immune cells in MASLD/MASH are not known.

Patients with MASLD/MASH and healthy volunteers have been prospectively enrolled in a cross-sectional study. Patients have been histologically stratified and further characterized by liver bulk RNA sequencing (RNA-Seq). Peripheral immune cells from patients and control blood samples have been comprehensively profiled using bulk and single RNA-Seq.

Twenty-two patients with fibrosis stage less than F3 have been histologically stratified into patients with low, medium, and high disease activity scores (NAFLD activity score [NAS]). In contrast to fibrosis, the NAS group correlated with noninvasive imaging readouts and blood biomarkers of liver damage and inflammation (ALT, AST). The prevalence of type 2 diabetes and obesity increased with the NAS stage. Bulk RNA-seq profiling of patient liver biopsies revealed gene signatures that were positively and negatively associated with NAS. Known marker genes for liver fibrosis where upregulated on RNA level. Blood bulk RNA-seq showed only moderate differences in patients versus healthy controls. In contrast, single-cell analysis of white blood cells revealed multiple alterations of immune (sub-)populations, including an increased abundance of immature B cells and myeloid suppressor cells in patients with MASLD/MASH as compared to healthy controls.

The study gives new insights into the pathophysiology of MASLD/MASH already manifesting relatively early in peripheral immune cell compartments. This opens new avenues for the development of new biomarker diagnostics and disease therapies.

Non-alcoholic fatty liver disease (NAFLD) accounts for remarkable burden of death and costs worldwide with no recommended pharmacological intervention for the clinical management. This study aimed to investigate the efficacy and underlying mechanisms of rhubarb-derived polysaccharides (RP) in mitigating high-fat diet (HFD)-induced NAFLD and to analyze the primary monosaccharide components of RP. Forty male C57BL/6 mice were subjected to a dietary intervention consisting of either a high fat or chow diet for a duration of 12 weeks. RP (270, 540 mg·kg-1·d-1) was administered to the mice for 4 consecutive weeks from the 9th week. Various assessments were conducted, including histopathological examination, liver transcriptome analysis, non-targeted metabolomics analysis, and evaluation of protein expressions related to lipid and bile acid metabolism. This study found RP demonstrate a protective effect on the livers of NAFLD mice by inhibiting lipid accumulation and reducing hepatocyte inflammatory damage. The metabolomics analysis of multi-tissues revealed that the RP exert a hepatoprotective effect against NAFLD by restoring the altered bile acids (BAs) and fatty acids (FFAs) metabolism through the improvement of BA transporter, nucleus hormone receptor, lipogenesis protein, FFA transporter, and lipolysis proteins. Hence, RP may serve as a potential therapeutic agent for NAFLD.

We aimed to assess the efficacy and safety of Aldafermin in treating patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH).

We searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing Aldafermin to placebo for treating patients with MASH up to December 8, 2024. The risk ratios (RR) with 95 % confidence intervals (CI) were pooled for binary outcomes using a random-effects model. Additionally, we conducted subgroup analysis by fibrosis stage and Aldafermin dosage, and meta-regression analysis assuming the dosage of Aldafermin as a covariate.

We included 4 RCTs, encompassing 491 patients. Compared to placebo, Aldafermin had a higher probability of MASH resolution without worsening of fibrosis (RR 3.04; 95 %CI 1.12-8.28), composite of fibrosis improvement and MASH resolution (RR 5.86; 95 %CI 1.15-29.94), and reduction ≥30 % in hepatic fat fraction by MRI-PDFF (RR 3.14; 95 %CI 1.44-6.85). There were no significant differences in fibrosis improvement ≥1 stage without worsening of MASH (RR 1.48; 95 %CI 0.93-2.35), and overall AEs (RR 1.02; 95 %CI 0.95-1.11) between the groups. Subgroup analysis by fibrosis stage and Aldafermin dosage showed consistent results, and meta-regression analysis by dosage showed a dose-dependent improvement for the outcome of ≥30 % reduction in hepatic fat fraction by MRI-PDFF.

In conclusion, Aldafermin improved MASH resolution without worsening fibrosis, enhanced the composite of fibrosis improvement and MASH resolution, reduced hepatic fat fraction by MRI-PDFF, and was safe for treating patients with biopsy-confirmed MASH compared to placebo.

Metabolic syndrome is a cluster of some conditions such as high blood sugar, high blood triglycerides, low HDL cholesterol, abdominal obesity, and high blood pressure. Introducing a drug or a food that manages the majority of these medical conditions is invaluable. Tinospora cordifolia, known as guduchi and giloy, is a medicinal herb in ayurvedic medicine that is used in the treatment of various diseased conditions and also as a food for the maintenance of health. Here, we reviewed the current evidence supporting the role of giloy in the development and treatment of metabolic syndrome components. Appropriate articles that have been published until May 2024 were carefully extracted from PubMed, Scopus, and WOS databases to write a narrative review systematically. Gathered data showed the beneficial effects of giloy on metabolic syndrome components: hyperlipidemia, obesity, atherosclerosis, hypertension, and especially diabetes mellitus. As diabetes and insulin resistance seem to be a central feature of metabolic syndrome and in turn, can cause dyslipidemia, obesity, and, atherosclerosis, these beneficial effects are predictable with the anti-diabetogenic property of giloy. In this review, the main mechanisms of action of giloy in metabolic syndrome components are discussed. Based on the results, although giloy has been less investigated, considerable studies provide evidence of its beneficial effects on different components of metabolic syndrome. Relevant clinical trials are necessary to validate the mentioned effects, safety, and optimum dose of this herbal medicine and its components in managing different components of metabolic syndrome and transition from bench to bedside.

The liver accounts for almost 95% of lipid metabolism in broilers and serves as a crucial metabolic organ. Stress, which occurs when broilers are exposed to a heated environment, inhibits liver metabolism, significantly impacting their growth. This experiment investigated the combination of GBE with TP to improve hepatic lipid metabolism in heat-stressed broiler chickens by inhibiting the AMPK/SREBP-1C/ACC pathway. Three hundred broilers were reared usually until 21 days and randomly divided into six groups, namely CON group, HS group, TP group (300 mg/kg), GBE100 group (GBE100 mg/kg + TP300 mg/kg), GBE300 group (GBE 300 mg/kg + TP 300 mg/kg), GBE600 (600 mg/kg + TP 300 mg/kg) groups, where the CON group was kept at 23 °C, and the HS group and the TP, GBE100, GBE300, and GBE600 groups of each medication group were kept at 35 ± 2 °C for 10 h per day. Liver and serum samples were extracted at 28 and 42 days of age, respectively. The results showed that, at 42 days of age, the GBE600 group exhibited significantly superior performance to the HS group in ADG, ADFI, and F/G (p < 0.01). Serum TG, TC, and LDL-C levels were significantly lower (p < 0.01), while HDL-C levels were significantly higher (p < 0.05). Additionally, the mRNA expression levels of LKB1, AMPK, SREBP-1C, and ACC were markedly reduced (p < 0.01). In contrast, the mRNA expression of HSL and CPT1A was significantly elevated (p < 0.01), indicating that the GBE600 was more effective in mitigating heat stress in broiler chickens at 42 days of age. It showed that the GBE600 was more effective in ameliorating heat stress in broilers at 42 days of age, thus providing an ethical basis for ameliorating the flocculation of hepatic lipid metabolism in heat-stressed broilers.

Despite advances in research, studies on predictive models for Non-Alcoholic Fatty Liver Disease (NAFLD)-related fibrosis remain limited. Identifying new biomarkers to distinguish Non-Alcoholic Steatohepatitis (NASH) from NAFLD would aid in the treatment of NASH. Gene expression and clinical profiles of NAFL and NASH patients were collected from databases. Differentially expressed genes with prognostic value were used to construct predictive model. Validation of fibrosis stage-related pyroptosis-related genes (PRGs) was performed using Sprague-Dawley rats liver fibrosis models induced by CCl4 or PS. Immune cell infiltration assessment demonstrated that stromal score, immune score, and ESTIMATE score were higher in patients with NASH compared to those with NAFL. BAX, BAK1, PYCARD, and NLRP3 were identified as hub genes that exhibit a strong correlation with fibrosis stage. Additionally, the expression of these genes was increased in fibrotic liver tissues induced by CCl4 and PS. The pyroptosis-associated gene signature effectively predicts the degree of liver fibrosis in NASH patients. Our study indicates that BAX, BAK1, PYCARD, and NLRP3 might serve as biomarkers for NASH-associated fibrosis.

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.

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.

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.

CHR is positively associated with gallstones, with MAFLD partially mediating this relationship. Managing CHR levels and preventing MAFLD may reduce gallstone incidence.

Organelles, despite having distinct functions, interact with each other. Interactions between organelles typically occur at membrane contact sites (MCSs) to maintain cellular homeostasis, allowing the exchange of metabolites and other pieces of information required for normal cellular physiology. Imbalances in organelle interactions may lead to various pathological processes. Increasing evidence suggests that abnormalorganelle interactions contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the key role of organelle interactions in NAFLD has not been fully evaluated and researched. In this review, we summarize the role of organelle interactions in NAFLD and emphasize their correlation with cellular calcium homeostasis, lipid transport, and mitochondrial dynamics.

The high-sensitivity C-reactive protein to albumin (CAR) ratio is a comprehensive measure of inflammation in vivo. Hepatic steatosis and fibrosis are significantly correlated with inflammation. The present study aimed to explore the possible associations between CAR and hepatic steatosis and fibrosis in the American population.

The study population involved the National Health and Nutrition Examination Survey (NHANES) participants from 2017 to 2020. The natural logarithm of CAR, calculated as Ln(CAR) with base "e," was used for further analyses. The relationships between Ln(CAR) and the controlled attenuation parameter (CAP) and between Ln(CAR) and liver stiffness measurement (LSM) were investigated through multivariate linear regression analysis. Interaction and subgroup analysis identified factors affecting these variables. Nonlinear relationships were elucidated by smoothing curves and threshold effect analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performance of the CAR for non-alcoholic fatty liver disease (NAFLD). The results were adjusted for U.S. population estimates.

The study included a total of 7,404 individuals. Ln(CAR) was positively correlated with CAP in the fully adjusted model, with an effect value of β = 1.827 (95% CI, 0.611, 3.042). A more pronounced positive association was observed among participants with a BMI ≥ 25 kg/m2 in the subgroup analysis. An inverted U-shaped association was shown between Ln(CAR) and CAP through smooth curve fitting and a two-segment linear regression model, with an inflection point of (-9.594). ROC curve analysis showed that CAR had a moderate predictive value for NAFLD (AUC = 0.6895), with a sensitivity of 0.7276 and a specificity of 0.6092. No significant association was detected between Ln(CAR) and the LSM.

We demonstrate an inverted U-shaped relationship between Ln(CAR) and CAP risk within the U.S. demographic. Our results suggest that CAR may serve as a valuable diagnostic tool for NAFLD. Further prospective research is necessary to validate this conclusion.

Non-alcoholic fatty liver disease (NAFLD) affects about 25% of adults worldwide. Its advanced form, non-alcoholic steatohepatitis (NASH), is a major cause of liver fibrosis, but there are no non-invasive tests for diagnosing or preventing it. In our study, we analyzed data from multiple sources to find crucial genes linked to NASH fibrosis. We built diagnostic models using 103 machine learning algorithms and validated them with two external datasets. All models performed well, with the best one (RF + Enet[alpha = 0.6]) achieving an average AUC of 0.822. This model used five key genes: LUM, COL1A2, THBS2, COL5A2, and NTS. Our findings show that these genes are important in collagen and extracellular matrix pathways, shedding light on how NASH progresses to liver fibrosis. We also found that certain immune cells, like M1 macrophages, are involved in this process. This study provides a reliable diagnostic tool for assessing fibrosis risk in NASH patients and suggests potential for immunotherapy, laying a foundation for future treatments.

Non-alcoholic fatty liver disease (NAFLD) is a common type of chronic liver disease and its incidence is increasing. Its disease progression is closely related to non-alcoholic steatohepatitis and liver fibrosis. Effective treatment is currently lacking. The traditional Chinese medicine ginseng (Panax ginseng) shows unique advantages in NAFLD intervention, but its complex compositional system and molecular mechanism network still need to be systematically analyzed.

This paper systematically integrates evidence from nearly 20 years of research to elucidate the multi-target pharmacological mechanism of ginseng for the treatment of NAFLD.

Relevant information was sourced from Pubmed, Web of science, Embase and CNKI databases. Using BioRender and visio to draw biomedical illustrations.

The active ingredients of ginseng contain 2 classes of saponins (tetracyclic triterpene saponins, pentacyclic triterpene saponins and other modified types) and non-saponins. Different cultivation methods, processing techniques and extraction sites have expanded the variety of ginseng constituents and demonstrated different pharmacological activities. Studies have shown that ginseng and its functional components have the ability to regulate lipid metabolism disorders, inflammation, oxidative stress, endoplasmic reticulum stress, insulin resistance, disruption of intestinal flora structure, cell death and senescence. Demonstrates the potential of ginseng for the treatment of NAFLD.

This study reveals for the first time the integrative mechanism of ginseng in the treatment of NAFLD through the tertiary mode of action of "multi-component multi-target multi-pathway". The multilevel modulatory ability of ginseng provides a new direction for the development of comprehensive therapeutic strategies for NAFLD.

This study sought to examine the associations between cardiometabolic indices and the onset of metabolic dysfunction-associated steatotic liver disease (MASLD) as well as its progression to liver fibrosis.

This study comprised 25,366 subjects aged 18 years and older, free of MASLD at baseline, from the Dalian Health Management Cohort (DHMC). Cardiometabolic indices include cardiometabolic index (CMI), atherogenic index of plasma (AIP), triglyceride glucose (TyG), triglyceride glucose-body mass index (TyG-BMI), triglyceride glucose-waist circumference (TyG-WC) and triglyceride glucose-waist height ratio (TyG-WHtR). All participants were categorized into quartile groups based on cardiometabolic indices. Cox proportional hazards regression models and restricted cubic splines were employed to examine the relationship between cardiometabolic indices and the incidence of MASLD as well as its progression to liver fibrosis, and analyses were performed between different subgroups. Mediation analysis was employed to explore how obesity and inflammation serve as mediators in the connection between cardiometabolic indices and MASLD. To evaluate the predictive ability of cardiometabolic indices for the onset of MASLD, the time-dependent receiver operating characteristic (ROC) curve was utilized.

A total of 5378 (21.2%) individuals developed MASLD during the follow-up period of 82,445 person-years. Multivariates Cox regression analyses showed that participants in the highest quartile of cardiometabolic indices had greater risk of MASLD than those in the lowest quartile (CMI: HR = 6.11, 95% CI 5.45-6.86; AIP: HR = 4.58, 95% CI 4.11-5.10; TyG: HR = 3.55, 95% CI 3.21-3.92; TyG-BMI: HR = 13.55, 95% CI 11.80-15.57; TyG-WC: HR = 12.52, 95% CI 10.93-14.34; TyG-WHtR: HR = 11.37, 95% CI 9.96-12.98). TyG-BMI (HR = 1.36, 95% CI 1.18-1.57), but not other cardiometabolic indices, was associated with liver fibrosis. Mediation analysis indicated that BMI mediated 40.4%, 33.2%, 36.5%, - 10.4%, 37.4%, 48.5% of the associations between CMI, AIP, TyG, TyG-BMI, TyG-WC, TyG-WHtR and MASLD. Time-dependent ROC curves demonstrated that TyG-BMI had a superior predictive ability for MASLD onset compared to other indicators.

The risk of developing MASLD increases as the level of cardiometabolic indices increases. Obesity may serve as a mediating factor in the aforementioned association. TyG-BMI showed the strongest association with the onset of MASLD and its progression to liver fibrosis, proved to be outperformed other cardiometabolic indicators, and could be the best clinical non-invasive biomarker for early screening of MASLD and liver fibrosis.

To elucidate the regional distribution of metabolic dysfunction-associated steatohepatitis (MASH) fibrosis within the liver and to identify potential therapeutic targets for MASH fibrosis.

Liver sections from healthy controls, patients with simple steatosis and MASH patients were analysed using spatial transcriptomics integrated with single-cell RNA-seq.

Spatial transcriptomics analysis of liver tissues revealed that the fibrotic region (Cluster 9) was primarily distributed in lobules, with some fibrosis also found in the surrounding area. Integration of the single-cell-sequencing data set (GSE189175) showed a greater proportion of inflammatory cells (Kupffer cells and T cells) and myofibroblasts in MASH. Six genes, showing high- or low-specific expression in Cluster 9, namely, ADAMTSL2, PTGDS, S100A6, PPP1R1A, ASS1 and G6PC, were identified in combination with pathology. The average expression levels of ADAMTSL2, PTGDS and S100A6 on the pathological HE staining map were positively correlated with the increase in the degree of fibrosis and aligned strongly with the distribution of fibrosis. ADAMTSL2+ myofibroblasts play a role in TNF signalling pathways and in the production of ECM structural components. Pseudotime analysis indicated that in the early stages of MASH, infiltration by T cells and Kupffer cells triggers a significant inflammatory response. Subsequently, this inflammation leads to the activation of hepatic stellate cells (HSCs), transforming them into myofibroblasts and promoting the development of liver fibrosis.

This study is the first to characterise lineage-specific changes in gene expression, subpopulation composition, and pseudotime analysis in MASH fibrosis and reveals potential therapeutic targets for this condition.

During the hepatic histological progression in metabolic dysfunction-associated steatotic liver disease (MASLD), the immunological mechanisms play a the pivotal role, especially when progressing to metabolic dysfunction-associated steatohepatitis (MASH). The discovery of the stimulator of interferon genes (STING) marked a significant advancement in understanding the immune system.

We searched literature on STING involved in MASLD in PubMed to summarise the role of intrahepatic or extrahepatic STING signal pathways and the potential agonists or inhibitors of STING in MASLD.

Besides inflammation and type I interferon response induced by STING activation in the intrahepatic or extrahepatic immune cells, STING activation in hepatocytes leads to protein aggregates and lipid deposition. STING activation in hepatic macrophages inhibits autophagy in hepatocytes and promotes hepatic stellate cells (HSCs) activation. STING activation in HSCs promotes HSC activation and exacerbates liver sinusoidal endothelial cells (LSECs) impairment. However, it was also reported that STING activation in hepatic macrophages promotes lipophagy in hepatocytes and STING activation in HSCs leads to HSC senescence. STING activation in LSEC, inhibits angiogenesis. For extrahepatic tissue, STING signalling participates in the regulation of the intestinal permeability, intestinal microecology and insulin action in adipocytes, which were all involved in the pathogenesis of MASLD.

There're plenty of STING ligands in MASLD. How STING activation affects the intercellular conversation in MASLD deserves thorough investigation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a high incidence globally and is a major cause of cirrhosis and hepatocellular carcinoma, lacking of efficient interventions. Patients with MASLD exhibit exceeded serum levels of palmitic acid (PA). However, the association between PA and MASLD remains obscure.

Gene expression omnibus dataset analysis, western blotting, mRNA-sequencing, RT-qPCR, a click chemistry-immunoprecipitation-immunofluorescence system, ELISA, lipid extraction and UHPLC-MS/MS analysis, CyTOF mass cytometry, gene knockdown via lentivirus-mediated shRNA, and high-fat methionine and choline-deficient diet-fed WT and db/db mice models were used to reveal the expression and functions of Porcupine in MASLD development both in vitro and in vivo.

Our findings show that PA, as a crucial substrate for protein palmitoylation, induced the expression of palmitoyltransferase Porcupine in a time-dependent manner. This induction was closely associated with dysregulated lipid metabolism and stimulated inflammatory response observed in vitro. Porcupine protein levels were significantly increased in liver tissues from both MASLD mice models, which was predominantly localised in lipid droplet-rich hepatocytes. Pharmacological inhibition of Porcupine by Wnt974 markedly ameliorated the aberrant lipid accumulation and inflammatory response in mouse livers. Furthermore, increased Porcupine positively correlated with CD36 at protein levels, and its inhibition or knockdown decreased CD36 protein levels via mechanisms irrelevant to transcriptional regulation, but primarily dependent on protein palmitoylation.

The current study reveals that PA-induced Porcupine disrupts lipid metabolism and promotes inflammatory response during MASLD development, which can be ameliorated by the Porcupine inhibitor Wnt974. Therefore, Porcupine may be a potential pharmacological target for the treatment of MASLD.

Direct-acting antivirals (DAAs) effectively eradicate hepatitis C virus. This study investigated whether metabolic dysfunction influences the likelihood of fibrosis regression after DAA treatment in patients with chronic hepatitis C (CHC).

This multicenter, retrospective study included 8,819 patients diagnosed with CHC who were treated with DAAs and achieved a sustained virological response (SVR) between January 2014 and December 2022. Fibrosis regression was defined as a 20% reduction in noninvasive surrogates for liver fibrosis, such as liver stiffness (LS) measured by vibration-controlled transient elastography (VCTE) and the fibrosis-4 (FIB-4) score. Hypercholesterolemia (h-TC) was defined as >200 mg/dL.

The median age of the study population was 59.6 years, with a predominance of male patients (n=4,713, 57.3%). Genotypes 1, 2, and others were confirmed in 3,872 (46.2%), 3,487 (41.6%), and 1,024 (12.2%) patients, respectively. Diabetes mellitus (DM) was present in 1,442 (17.2%) patients and the median LS was 7.50 kPa (interquartile range, 5.30-12.50). Multivariate analysis revealed that the presence of DM and pre-DAA h-TC were independently associated with a decreased probability of fibrosis regression by VCTE. Additionally, pre-DAA h-TC was independently associated with a decreased probability of fibrosis regression by the FIB-4.

Metabolic dysfunction has an unfavorable influence on fibrosis regression in patients with CHC who achieve SVR after DAA treatment.

The potential health benefits of sea buckthorn polyphenols (SBP) have been extensively studied, attracting increasing attention from researchers. This paper reviews the composition of SBP, the effects of processing on SBP, its interactions with nutrients, and its protective role in the gastrointestinal tract. Polyphenols influence nutrient absorption and metabolism by regulating the intestinal flora, thereby enhancing bioavailability, protecting the gastrointestinal tract, and altering nutrient structures. Additionally, polyphenols exhibit anti-inflammatory and immunomodulatory effects, promoting intestinal health. The interaction between polyphenols and intestinal flora plays a significant role in gastrointestinal health, supporting the composition and diversity of the gut microbiota. However, further research is needed to emphasize the importance of human trials and to explore the intricate relationship between SBP and gut microbiota, as these insights are crucial for understanding the mechanisms underlying SBP's benefits for the gastrointestinal tract (GIT).

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver disease globally, with inflammation and nutrition playing key roles in its progression. The Advanced Lung Cancer Inflammation Index (ALI) is a novel biomarker reflecting nutritional and inflammatory status. This study aims to explore the association between ALI and the risk of liver fibrosis and prognosis in MAFLD patients.

This cross-sectional study analyzed NHANES data from the 1999-2018 on adult participants in the US. Weighted logistic regression assessed the association between ALI and liver fibrosis risk. Mortality outcomes, including all-cause, cardiovascular disease (CVD), and cancer mortality, analyzed using weighted Kaplan-Meier and Cox proportional hazards models. Restricted cubic splines (RCS) and threshold effect analyses were uesd to explore non-linear relationships. Receiver operating characteristic (ROC) curve evaluated the prognostic value of ALI, and stratified analyses examined subgroup differences.

A total of 6,858 MAFLD patients (mean age 51.38 ± 17.22 years, 54% male) were included. A non-linear relationship was found between ALI and liver fibrosis risk, with a threshold at 5.68, beyond which the risk increased significantly (OR = 2.35, 95% CI: 1.89-2.95). Stronger associations were observed in subgroups with central obesity and prediabetes (P for interaction < 0.05). ALI was inversely associated with all-cause mortality (HR = 0.64, 95% CI: 0.56-0.72) and CVD mortality (HR = 0.57, 95% CI: 0.46-0.65), but not cancer mortality. RCS analysis showed an L-shaped non-linear relationship with all-cause mortality (threshold at 5.36) and a linear relationship with CVD mortality. Low HDL cholesterol and excessive alcohol consumption influenced the association between ALI and all-cause mortality (P for interaction < 0.05). ALI demonstrated the highest predictive accuracy for CVD mortality.

ALI is associated with an increased risk of liver fibrosis and reduced all-cause and CVD mortality, highlighting its potential value in assessing MAFLD prognosis, particularly CVD-related mortality.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern with limited therapeutic options. Multivitamins, widely consumed dietary supplements, have been proposed to modulate oxidative stress and inflammation, potentially impacting MASLD progression. However, their efficacy in reducing mortality and other complications in MASLD remains unclear. Using data from the UK Biobank with 7 years of median follow-up period, this study assessed the association between multivitamin use and health outcomes, including all-cause mortality, liver-related mortality, cardio-cerebrovascular disease (CVD), and chronic kidney disease (CKD), in individuals with MASLD and those without steatotic liver disease. Inverse probability of treatment weighting (IPTW) was employed to adjust for confounders. Multivitamin users showed a significantly lower all-cause mortality risk in the MASLD cohort both before (HR: 0.88, 95% CI 0.81-0.95, P = 0.034) and after (HR: 0.94, 95% CI 0.88-1.00, P = 0.037) IPTW adjustment. Multivitamin use was also associated with the lower risk of CVD (HR: 0.72, 95% CI 0.68-0.76, P < 0.001) and CKD (HR: 0.73, 95% CI 0.67-0.81, P < 0.001) in the MASLD cohort. No significant reduction was found for liver-related mortality or liver cirrhosis incidence. These findings suggest that multivitamins might provide broader protective effects in populations with metabolic dysfunction. Further research is needed to clarify their role in liver-specific outcomes.

Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.