The natural flavonoid quercetin, which exhibits a range of biological activities, has been implicated in liver disease resistance in recent research. In vivo study attesting to quercetin's protective effect against metabolic-associated fatty liver disease (MAFLD) is inadequate, however. Here, our investigation explored the potential benefits of quercetin in preventing MAFLD in C57BL/6 mice fed a high-fat diet (HFD). The results revealed that quercetin ameliorated the aberrant enhancement of body and liver weight. The hepatic histological anomalie induced by MAFLD were also mitigated by quercetin. HFD-induced imbalance in serum LDL, HDL, AST, ALT, TG, and LDH was mitigated by quercetin. Mechanically, we found that quercetin improved lipid metabolism by reducing lipogenesis proteins including ACC, FASN, and SREBP-1c and enhancing β-oxidation proteins including PPARα and CPT1A. In vitro study demonstrated that quercetin regulated hepatic lipid metabolism by targeting SREBP-1c and PPARα. Additionally, quercetin enhanced the antioxidant capacity in HFD-treated mice by downregulating Nrf2 and HO-1 expressions and upregulating SOD and GPX1 expressions. The hyper-activation of inflammation was also restored by quercetin via eliminating the phosphorylation of IκBα and NF-κB p65. Collectively, our observations highlight that quercetin exerts hepatoprotective properties in MAFLD mice by regulating hepatic lipid metabolism, oxidative stress and inflammatory response.

Metabolic-dysfunction-associated fatty liver disease (MAFLD) represents a broad spectrum of liver lipid metabolism disorders associated with metabolic homeostasis, inflammation, oxidative stress, and fibrogenesis. The incidence of MAFLD has increased in recent years, but there is a lack of effective treatment strategies. GSK621 shows potential as a novel adenosine-monophosphate-activated protein kinase (AMPK) agonist; however, its function in lipid metabolism has not yet been confirmed.

This study aimed to determine the effects of GSK621 on liver lipid accumulation in vitro and vivo and explore the underlying mechanism of these effects.

The function of GSK621 in lipid deposition was investigated in vitro with HepG2 cells and normal mouse liver cells (AML12), and in vivo using C57BL/6 J mice fed with a high-fat diet (60 % fat) for 8 weeks to establish a model of MAFLD, followed by GSK621 treatment for a further 8 weeks.

GSK621 treatment significantly improved hepatocyte steatosis via the AMPK-carnitine palmitoyl transferase 1 (CPT1A) pathway and decreased levels of reactive oxygen species (ROS) in cells, accompanied by elevated expression of antioxidative stress proteins. MAFLD mice showed significant improvements in liver steatosis after GSK621 treatment, as well as increased expression of liver proteins related to the AMPK pathway and antioxidative stress.

GSK621 can improve hepatocytes steatosis in vitro and vivo via the AMPK-CPT1A pathway by increasing lipid metabolism and augmenting expression of antioxidant-stress-related proteins to reduce ROS deposition.

Obesity, diabetes, and their cardiovascular and hepatic comorbidities are alarming public health issues of the twenty-first century, which share mitochondrial dysfunction, oxidative stress, and chronic inflammation as common pathophysiological mechanisms. An increasing body of evidence links the combined exposure to multiple environmental toxicants with the occurrence and severity of metabolic diseases. Endocrine disruptors (EDs) are ubiquitous chemicals or mixtures with persistent deleterious effects on the living organisms beyond the endocrine system impairment; in particular, those known as metabolism-disrupting chemicals (MDCs), increase the risk of the metabolic pathologies in adult organism or its progeny. Being largely lipophilic, MDCs mainly target the adipose tissue and elicit mitochondrial dysfunction by interfering with mitochondrial bioenergetics, biogenesis, dynamics and/or other functions. Plastics, when broken down into micro- and nano-plastics (MNPs), have been detected in several human tissues, including the liver. The harmful interplay between inflammatory and redox processes, which mutually interact in a positive feed-back loop, hence the term oxidative inflammation ("OxInflammation"), occurs both at systemic and organ level. In both liver and adipose tissue, oxinflammation contributes to the progression of the metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, it has been reported that individuals with MASLD may be more susceptible to the harmful effects of toxicants (mainly, those related to mitochondria) and that chronic exposure to EDs/MDCs or MNPs may play a role in the development of the disease. While liver has been systematically investigated as major target organ for ambient chemicals, surprisingly, less information is available in the literature with respect to the adipose tissue. In this narrative review, we delve into the current literature on the most studied environmental toxicants (bisphenols, polychlorinated biphenyls, phthalates, tolylfluanid and tributyltin, per-fluoroalkyl and polyfluoroalkyl substances, heavy metals and MNPs), summarize their deleterious effects on adipose tissue, and address the role of dysregulated mitochondria and oxinflammation, particularly in the setting of MASLD.

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing because people's dietary habits are dominated by high caloric intake and sedentary lifestyles, leading to the accumulation of lipid, reactive oxygen species (ROS) and inflammation. However, treating MASH remains a challenge.

Two-dimensional (2D) niobium carbide (Nb4C3) MXene nanoenzymes (MXenzymes) possess both antioxidant and anti-inflammatory properties and have attracted considerable attention in the tumor and engineering fields. The Nb4C3 MXenzyme was developed for MASH therapy and exhibited biosafety and antilipid peroxidation activity.

Nb4C3 reduced excessive ROS and proinflammatory cytokine levels through its antilipid peroxidation activities, resulting in the inhibition of hepatocyte lipid accumulation and inflammation in a methionine-choline-deficient diet (MCD)-induced murine MASH model. Mechanistically, Nb4C3 not only inhibited lipid accumulation and disrupted lipid metabolism in hepatocytes but also attenuated fatty acid-induced cell death by reducing intracellular ROS levels, which significantly promoted the polarization of M1 macrophages to M2 macrophages by alleviating oxidative stress and suppressing inflammatory factor expression.

The Nb4C3 MXenzyme can be used as a multifunctional bioactive material to alleviate hepatic steatosis and inflammation in MASH mice through its robust antioxidant and anti-inflammatory activities.

This study aimed to explore the efficacy and mechanisms of raspberry (Rubus idaeus L. fruit) aqueous extract (RE) in alleviating high-fat diet (HFD)-induced metabolic-associated fatty liver disease (MAFLD). The MAFLD mouse model was established to examine the effects of RE through liver transcriptome and metabolomics analysis. In this study, RE supplementation significantly alleviated HFD-induced liver injury, hepatosteatosis, inflammation, and insulin resistance. Liver transcriptome analysis demonstrated that RE supplementation favorably regulated signaling pathways involved in fatty acid metabolism and inflammation, including the AMPK signaling pathway, PPAR signaling pathway, apoptosis, etc. Furthermore, the injection of compound C, an antagonist of AMPK, notably reversed the hepatoprotective effects of RE, evidenced by increased lipid profile levels, accelerated fatty acid-related gene disorder, and increased positive tunnel staining area. Furthermore, liver metabolomics analysis demonstrated that RE treatment led to substantial enrichment of the liver tissue metabolite umbelliferone (UMB), which has the potential to ameliorate lipid accumulation and hepatocyte injury through the AMPK signaling pathway. In summary, RE intervention mitigated HFD-induced liver dysfunction in mice, with UMB likely being the primary component responsible for its therapeutic efficacy in the liver. In addition, this study provided new insights, suggesting that RE could be used as a promising therapeutic approach for modulating MAFLD via apoptosis and the AMPK/PPARα signaling pathway.

Metabolic dysfunction-associated fatty liver disease (MAFLD), which is characterized by hepatocyte lipid accumulation driven by systemic metabolic dysregulation, represents a critical therapeutic challenge in the context of the global metabolic syndrome epidemic. The clinically recommended drugs for MAFLD mainly include antioxidants, hepatoprotective anti-inflammatory drugs, and weight-loss drugs. However, the mechanisms underlying the progression of MAFLD is characterized by nonlinearity, highlighting the urgent need for safer multi-target alternative therapies. Although existing single-target pharmacological interventions often show limited efficacy and adverse effects, the multi-component and multi-target nature of the active ingredients in traditional Chinese medicine (TCM) formulations represent new opportunities for systemic metabolic regulation. In this study, by searching PubMed and Web of Science, we identified 108 experimental studies. By evaluating multiple mechanisms, such as improving lipid metabolism and insulin resistance, alleviating oxidative stress damage, inhibiting liver inflammation, suppressing liver fibrosis, reducing endoplasmic reticulum stress, regulating hepatocyte autophagy, inhibiting hepatocyte apoptosis, improving mitochondrial dysfunction, and regulating the intestinal flora, we constructed a cross-scale regulatory network for the treatment of MAFLD by the active components of TCM. Subsequently, the dynamic target groups were screened, and a new paradigm of "mechanism-oriented and spatiotemporal-optimized" design for TCM compound prescriptions was proposed, providing a theoretical framework for the development of precise therapies that can improve liver lipid metabolism, block inflammation and fibrosis, and restore intestinal homeostasis.

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.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) among individuals with hyperuricemia is significantly high. The aim of this study was to identify effective biomarkers for the detection of MASLD among patients with hyperuricemia.

We conducted an analysis involving 3424 participants with hyperuricemia from the National Health and Nutrition Examination Survey (1999-2020). To identify potential significant variables, we employed Boruta's algorithm, SHapley Additive exPlanations (SHAP) and random forests. Multivariable logistic regression models were utilized to assess the odds ratio (OR) of developing MASLD. To evaluate the accuracy and clinical value of our prediction model, we employed receiver operating characteristic (ROC) curves and decision curve analysis (DCA) curves.

Among the study population of 3424 participants (mean [SD] age, 54 [20] years, 1788 [52.22%] males) with hyperuricemia, 1670 participants had MASLD. Using Boruta's algorithm, SHAP and random forests, our analysis suggested that Triglyceride Glucose-Waist Circumference (TyG_WC) was one of the most significant variables in predicting MASLD risk, with an area under the receiver operating characteristic (AUROC) of 0.865. The restricted curve spline (RCS) revealed a positive association between the odds ratio of TyG_WC and MASLD, when compared with lowest quantile of TyG_WC, the risk of MASLD for highest quantile was 137.96 times higher. The predictive strategy incorporating TyG_WC notably enhanced the clinical model, with threshold probabilities spanning from approximately 0% to 100%, resulting in a significant improvement of the net benefit.

Our analysis found that TyG_WC was one of the most significant variables in predicting MASLD risk among individuals with hyperuricemia.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the main cause of chronic liver disease. Baicalin (Bai), a bioactive molecule found in Scutellaria baicalensis Georgi, possesses antioxidant and antiinflammatory properties. These activities suggest Bai could be a promising therapeutic agent against NAFLD; however, its specific effects and underlying mechanism are still not clear. This study aims to explore the effect of Bai to attenuate MAFLD and associated molecular mechanisms. Bai (50, 100 or 200 mg/kg) was orally administered to db/db mice with MAFLD for 4 weeks or db/m mice as the normal control. Bai markedly attenuated lipid accumulation, cirrhosis and hepatocytes apoptosis in the liver tissues of MAFLD mice, suggesting strong ability to attenuate MAFLD. Bai significantly reduced proinflammatory biomarkers and enhanced antioxidant enzymes, which appeared to be modulated by the upregulated p62-Keap1-Nrf2 signalling cascade; furthermore, cotreatment of Bai and all-trans-retinoic acid (Nrf2 inhibitor) demonstrated markedly weakened liver protective effects by Bai and its induced antioxidant and antiinflammatory responses. The present study supported the use of Bai in attenuating MAFLD as a promising therapeutic agent, and its strong mechanism of action in association with the upregulating the p62-keap1-Nrf2 pathway.

The interplay between immune cells and metabolic associated fatty liver disease (MAFLD) is a critical research frontier, bridging immunology and hepatology. The bibliometric findings can guide future research and funding priorities in the field by highlighting key areas of focus and potential therapeutic targets.

To analyze the literature on immune cells and MAFLD, identifying research trends and future hotspots.

A systematic search in the Web of Science Core Collection from January 1, 2004 to May 20, 2024, yielded 1936 articles on immune cells and MAFLD. Excluding non-research documents, the data were analyzed using R packages Cluster profiler, enrichplot, ggplot2, VOSviewer and CiteSpace. Visualizations were created for countries, institutions, authors, journals, fields, co-cited references, keywords, genes, and diseases, with gene a disease data from Citexs.

The field gained momentum in 2006, with the United States of America and China as leading contributors. Key research themes included oxidative stress, metabolic syndrome, liver fibrosis, and the role of Kupffer cells. Bioinformatics identified interleukin-6, tumor necrosis factor and signal transducer and activator of transcription 3 as central proteins in immune responses and inflammation, suggesting potential therapeutic targets for MAFLD. Clinically, these hub genes play pivotal roles in the pathogenesis of MAFLD. For instance, targeting the tumor necrosis factor signaling pathway could reduce inflammation, while modulating interleukin-6 and signal transducer and activator of transcription 3 expression may improve metabolic function, offering new strategies for MAFLD therapy.

This bibliometric analysis reports on the research hotspots and emerging trends in the field of immune cells and MAFLD, highlighting key proteins and potential therapeutic strategies through bioinformatics.

Obesity and diabetes are risk factors for severe dengue. As there are limited data on the association of obesity with liver dysfunction and oxidative stress in patients with acute dengue, we investigated liver dysfunction associated with obesity, oxidative stress and inflammatory markers, in a large cohort of patients with varying severity of acute dengue.

577 adults dengue patients with acute disease, presenting with a duration of illness ≤ 4 days, were enrolled and followed up from admission to discharge, with clinical and laboratory features recorded. Aspartate transaminase (AST), alanine transaminase (ALT), C-reactive protein, ferritin, 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) levels were measured, along with the height, weight and waist circumference.

AST, ALT, CRP and ferritin levels were significantly higher in patients with central obesity (waist circumference of ≥80cm in women or ≥90cm in men) compared to leaner individuals. ALT and CRP levels were also significantly higher in patients with a BMI of ≥ 23.9 kg/m2. 4-HNE levels significantly increased with the rise in AST levels and with ALT levels although not significant. In contrast, MDA levels gradually decreased with the rise in AST levels and ALT levels. There were no differences in 4-HNE and MDA levels in relation to clinical disease severity. However, MDA levels were significantly higher in younger individuals, and leaner individuals with a normal BMI. Furthermore, MDA levels inversely correlated with serum ferritin levels, while AST, ALT and CRP levels significantly correlated ferritin levels.

4-HNE and MDA which are markers of lipid peroxidation, appear to play different roles in the pathogenesis of dengue, which should be further investigated for identification of therapeutic targets for treatment of dengue.

Treating metabolic dysfunction-associated fatty liver disease (MAFLD) and reducing the occurrence of MAFLD-associated liver cancer remain challenging. Two-dimensional (2D) tantalum carbide (Ta4C3) MXene nanozymes (MXenzymes) exhibit antioxidant and anti-inflammatory activities and have thus attracted considerable attention in the fields of oncology and engineering. However, the potential mechanism of action and bioactive properties of Ta4C3 in MAFLD remain uncertain. In our study, Ta4C3 not only inhibited lipid accumulation and disrupted lipid metabolism in hepatocytes but also reduced cell death caused by fatty acids by decreasing intracellular reactive oxygen species (ROS) levels, which significantly promoted the polarization of M1 macrophages to M2 macrophages by alleviating oxidative stress and further suppressing inflammatory factor expression. In mice fed a methionine-choline-deficient (MCD) diet, Ta4C3 reduced lipid accumulation, the infiltration of inflammatory cells, and liver cell apoptosis by modulating the cellular microenvironment through its anti-inflammatory and antioxidant properties. Therefore, Ta4C3 can be used as a multifunctional bioactive material to alleviate hepatic steatosis and inflammation in individuals with MAFLD/metabolic dysfunction-associated steatohepatitis (MASH) because of its robust antioxidant and anti-inflammatory effects.

(1) Background: Hepatic lipid accumulation is the initial factor in metabolic-associated fatty liver disease (MAFLD) in type 2 diabetics, leading to accelerated liver damage. The NOD-like receptor protein 3 (NLRP3) inflammasome plays a critical role in this process. Dapansutrile (DAPA) is a novel NLRP3 inflammasome inhibitor; however, its effect on ectopic lipid accumulation in the liver remains unclear. This study aimed to investigate the therapeutic effect of DAPA on hepatic lipid accumulation in a diabetic mouse model and its potential mechanisms. (2) Methods: The effects of DAPA on hepatic ectopic lipid deposition and liver function under metabolic stress were evaluated in vivo using db/db and high-fat diet (HFD) + streptozotocin (STZ) mouse models. Additionally, the role and mechanism of DAPA in cellular lipid deposition, mitochondrial oxidative stress, and inflammation were assessed in HepG2 cells treated with free fatty acids (FFA) and DAPA. (3) Results: Our findings indicated that DAPA treatment improved glucose and lipid metabolism in diabetic mice, particularly addressing liver heterotopic lipid deposition and insulin resistance. DAPA treatment also ameliorated lipid accumulation and mitochondrial-related functions and inflammation in HepG2 cells through the NLRP3-Caspase-1 signaling axis. (4) Conclusions: Targeting NLRP3 with DAPA may represent a novel therapeutic approach for diabetes-related fatty liver diseases.

The efficacy and safety of a lower dose of vitamin E for metabolic dysfunction-associated steatohepatitis (MASH) treatment are unclear. This multi-center, randomized, double-blind, placebo-controlled study includes 124 non-diabetic participants with biopsy-proven MASH. Participants are randomly assigned to receive oral vitamin E 300 mg or the placebo in a 1:1 ratio. The primary outcome is improvement in hepatic histology. In the modified intention-to-treat population, 29.3% of participants in the vitamin E group achieve the primary outcome compared with 14.1% in the placebo group. Significant improvement in steatosis, lobular inflammation, and fibrosis stages is observed in the vitamin E group. 12 serious adverse events are reported in this trial but are not considered to be related to the treatment. Vitamin E 300 mg daily achieves sound improvements in liver histology in the Chinese population with MASH. This study is registered at ClinicalTrials.gov (NCT02962297).

Metabolic dysfunction-associated steatohepatitis (MASH) is a large group of metabolic diseases that are hazardous to human health. Endothelial-to-mesenchymal transition (EndMT) mediated myofibroblast activation is an important factor that aggravates the development of liver fibrosis during MASH. However, the limited understanding of the underlying molecular mechanisms that drive EndMT in MASH has hindered the development of molecularly targeted therapies specifically targeting this pathological process.

We employed wild-type and ifn-γ-deficient mice, MASH models were induced repeated CCl4 injections and a high-fat diet to verify the significance of IFN-γ role in vivo and its impact in EndMT. Male mice models of MASH were used to further analyze the effect of Scutellarin@BSA on the improvement of liver fibrosis during MASH in vivo and HUVECs were used to assess IFN-γ effect on EndMT and its interaction with JAK signaling pathway in vitro.

The results showed that IFN-γ is revealed as a key regulator of EndMT during MASH, as evidenced by the significantly lower levels of EndMT and reduced pathological damage in the livers of ifn-γ knockout mice. Furthermore, our research has led to the development of Scutellarin@BSA therapy, which targets and mitigates IFN-γ-driven EndMT, which showed excellent therapeutic effects on EndMT and liver fibrosis in vivo and in vitro during MASH. Mechanistically, IFN-γ can directly bind to the JAK protein and activate downstream STAT1 transcription factors, exerting transcriptional activity and further driving the expression of EndMT-associated proteins. Notably, Scutellarin@BSA treatment effectively diminishes the hallmarks of liver fibrosis by modulating the canonical JAK/STAT1 signaling pathway.

IFN-γ was identified as a key regulator of EndMT, and Scutellarin@BSA, as an emerging treatment, has been found to effectively inhibit EndMT by directly targeting the regulatory influence of the IFN-γ signaling. This result demonstrates significant therapeutic efficacy in alleviating hepatic fibrosis during MASH, highlighting its great potential as an innovative liver fibrosis treatment.

This study aimed to investigate the association between high-sensitivity C-reactive protein (hsCRP) levels and hepatic fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and assess its predictive efficacy.

The study included 1,477 participants from the United States and 1,531 from China diagnosed with MASLD. Liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were assessed by vibration-controlled transient elastography (VCTE) to evaluate the presence and degree of hepatic fibrosis and steatosis. The relationship between hsCRP levels and hepatic fibrosis in MASLD patients was examined using multivariable-adjusted and restricted cubic spline (RCS) models. Additionally, subgroup analyses were conducted to investigate the potential heterogeneity among different characteristic subgroups.

The results demonstrated a significant correlation between elevated hsCRP levels and an increased risk of significant fibrosis, advanced fibrosis, and cirrhosis in the US cohort of MASLD patients (OR 2.22, 1.69, and 2.85, respectively; all P <0.05). The results of the Chinese cohort were consistent with those of the US cohort, and there was a significant and positive correlation between hsCRP levels and the risk of hepatic fibrosis in patients with MASLD (OR 2.53, 3.85, and 3.78, respectively, all P <0.001). The RCS analysis revealed a significant non-linear relationship between hsCRP levels and the degree of hepatic fibrosis, with disparate inflection point values observed across different cohorts (approximately 9 mg/L in the US cohort and 4 mg/L in the Chinese cohort). The impact of hsCRP levels on the risk of hepatic fibrosis varied across different subgroups with distinct characteristics.

The present study demonstrated a significant correlation between hsCRP levels and the degree of hepatic fibrosis in patients with MASLD, with notable dose-response relationships and subgroup differences.

Hypertension development and progression are largely influenced by inflammation, which plays a critical role by activating the immune system and causing damage to the vascular endothelium. Metabolic dysfunction-associated fatty liver disease (MAFLD) is also associated with chronic low-grade inflammation, which drives disease progression via metabolic imbalances and adipose tissue dysfunction. This study investigates the relationship between inflammatory indices and MAFLD in hypertensive patients and assesses the predictive accuracy of these indices for MAFLD.

We performed a cross-sectional analysis involving 34,303 hypertensive patients from a Chinese hospital-based registry. The diagnosis of MAFLD was established using metabolic dysfunction criteria alongside evidence of hepatic steatosis confirmed through imaging. Complete blood counts were used to calculate inflammatory indices, including the monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic inflammatory response index (SIRI), systemic immune-inflammation index (SII), and aggregate index of systemic inflammation (AISI). To assess the relationship between inflammatory indices and MAFLD, multivariable logistic regression was performed with adjustments for potential confounders. The diagnostic performance of these indices was analyzed using receiver operating characteristic (ROC) curves and area under the curve (AUC) calculations.

Patients with MAFLD exhibited significantly elevated levels of all inflammatory indices compared to those without. After multivariable adjustment, each standard deviation increase in AISI, SIRI, and SII was associated with a 74%, 62%, and 58% increased odds of MAFLD, respectively. The AUC for AISI was 0.659, indicating moderate diagnostic accuracy. The AUCs for SIRI and SII were 0.626 and 0.619, respectively, while NLR, PLR, and MLR had lower AUCs of 0.593, 0.558, and 0.589, respectively.

In hypertensive patients, inflammatory indices, especially AISI, show a strong association with MAFLD, indicating their potential utility in risk stratification within clinical settings. Further research is needed to evaluate the effectiveness of these markers in the management of MAFLD.

Nonalcoholic steatohepatitis (NASH) has recently garnered increased attention due to immune infiltration. However, the role of membrane-associated protein 17 (MAP17) in NASH remains unclear, which prompted this study to explore its relationship with immune infiltration and its regulatory mechanisms.

We employed weighted correlation network analysis (WGCNA) to construct a gene co-expression network aimed at identifying key genes associated with NASH progression. Our further analyses included differential expression evaluation, protein-protein interaction (PPI) network analysis, and Venn diagram analysis to discover novel targets. The CIBERSORT algorithm assessed the correlation between MAP17 and immune cell infiltration within the tumor microenvironment (TME), while the TIDE algorithm predicted responses to immunotherapy. Additionally, we conducted gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) to elucidate the mechanisms by which MAP17 operates. The expression of MAP17 was validated using liver tissues obtained from NASH patients and mice with diet-induced NASH or CCl4-induced liver fibrosis.

Our findings identified MAP17 as a novel target in the progression of NASH. Correlation analyses demonstrated a positive association between MAP17 and M1 macrophage infiltration, as well as a negative association with M2 infiltration. TIDE results positioned MAP17 as a potential biomarker for predicting responses to immune checkpoint blockade. Mechanistic studies revealed that MAP17 induced oxidative stress, which subsequently activated the p53, PI3K-AKT, and Wnt signaling pathways. Validation analyses confirmed that MAP17 levels significantly increased in liver tissues of mice with diet-induced NASH or CCl4-induced liver fibrosis, as well as in NASH patients.

MAP17 is a novel biomarker linked to macrophage infiltration and immunotherapy responses in NASH patients. The oxidative stress induced by MAP17 activates the p53, PI3K-AKT, and Wnt pathways, all of which contribute to the progression of NASH.

Dysfunction in podocyte mitophagy has been identified as a contributing factor to the onset and progression of diabetic nephropathy (DN), and BMAL1 plays an important role in the regulation of mitophagy. Thus, this study intended to examine the impact of BMAL1 on podocyte mitophagy in DN and elucidate its underlying mechanisms.

High D-glucose (HG)-treated MPC5 cells was used as a podocyte injury model for investigating the potential roles of BMAL1 in DN. Mitophagy was examined by detecting autophagosomes using transmission electron microscopy, and detecting the colocalization of LC3 and Tom20 using immunofluorescence staining. The interaction between BMAL1 and SIRT1 was conducted by immunoprecipitation (Co-IP) assay.

In HG-induced podocyte injury model, we found that BMAL1 and SIRT1 mRNA level was significantly decreased, and positively correlated with mitophagy dysfunction. BMAL1 overexpression could ameliorate HG-induced podocyte injury, evidenced by improved cell viability, decreased cell apoptosis and inflammatory cytokines expression (TNF-α, IL-1β, and IL-6). BMAL1 overexpression could promote podocyte mitophagy coupled with increased expression of mitophagy markers PINK1 and Parkin. In terms of mechanism, Co-IP suggested that BMAL1 could interact with SIRT1. SIRT1 inhibitor Ex-527 addition obviously inhibit the effect of BMAL1 overexpression on the mitophagy, demonstrating that BMAL1 may act on mitophagy by SIRT1//PGC-1α axis.

Our in vitro experiments demonstrate that BMAL1/SIRT1/PGC-1α pathway may protect podocytes against HG-induced DN through promoting mitophagy.

The objective of this study was to investigate the association between sarcopenia and liver fibrosis in patients aged 18-59 years with metabolic dysfunction-associated steatotic liver disease (MASLD) and to assess the potential of sarcopenia as a risk factor for the progression of liver fibrosis.

The study included 821 patients with MASLD in the US cohort and 3,405 patients with MASLD in the Chinese cohort. Liver controlled attenuation parameters (CAP) and liver stiffness measurements (LSM) were assessed by vibration-controlled transient elastography (VCTE) to evaluate the extent of hepatic steatosis and fibrosis. Sarcopenia was assessed by measuring appendicular skeletal muscle mass (ASM) and calculating ASMI. To analyze the relationship between sarcopenia, ASMI, and liver fibrosis, logistic regression models, multivariate-adjusted models, and restricted cubic spline (RCS) models were employed, with stratification and interaction analyses.

The results demonstrated that patients with sarcopenia exhibited a markedly elevated risk of significant liver fibrosis, advanced liver fibrosis, and cirrhosis compared to those without sarcopenia in both cohorts. After adjusting for confounding variables, sarcopenia was identified as an independent risk factor for the progression of liver fibrosis in patients with MASLD. A significant negative correlation was observed between ASMI and the severity of liver fibrosis, with a progressive reduction in the risk of liver fibrosis associated with increasing ASMI. Additionally, a non-linear feature was evident in some liver fibrosis indicators. Subgroup analysis further corroborated the finding that the harmful effect of sarcopenia on liver fibrosis was consistent across all identified subgroups.

Sarcopenia may be associated with the progression of liver fibrosis in patients with MASLD. Monitoring ASMI may assist in identifying individuals at an elevated risk of liver fibrosis in MASLD patients.

Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is a broad condition characterized by lipid accumulation in the liver tissue, which can progress to fibrosis and cirrhosis if left untreated. Traditionally, liver biopsy is the gold standard for evaluating fibrosis. However, non-invasive biomarkers of liver fibrosis are developed to assess the fibrosis without the risk of biopsy complications. Novel serum biomarkers have emerged as a promising tool for non-invasive assessment of liver fibrosis in MAFLD patients. Several studies have shown that elevated levels of Mac-2 binding protein glycosylation isomer (M2BPGi) are associated with increased liver fibrosis severity in MAFLD patients. This suggests that M2BPGi could serve as a reliable marker for identifying individuals at higher risk of disease progression. Furthermore, the use of M2BPGi offers a non-invasive alternative to liver biopsy, which is invasive and prone to sampling errors. Overall, the usage of M2BPGi in assessing liver fibrosis in MAFLD holds great promise for improving risk stratification and monitoring disease progression in affected individuals. Further research is needed to validate its utility in clinical practice and establish standardized protocols for its implementation.

The pathophysiology of liver diseases is significantly influenced by oxidative stress, making its alleviation a key strategy for treatment. The Keap1/Nrf2 signaling pathway is the body's most crucial antioxidant defense mechanism. Traditional Chinese medicine, Desmodium heterocarpon (L.) DC, has shown promising hepatoprotective effects, however, the specific active components and underlying mechanisms of its liver-protective properties remain inadequately understood. Further investigation into the bioactive constituents and mechanisms of its hepatoprotective action is therefore essential.

This study aims to identify the active ingredients in D. heterocarpon and to explore its hepatoprotective properties and underlying mechanisms.

The hepatoprotective activity of the ethyl acetate fraction (JEAE) from D. heterocarpon was first evaluated utilizing a mouse model of acute liver damage (ALI) caused by CCl4. Molecular and histological analyses, including H&E staining, ELISA, and Western blot, were used to assess liver protection. The chemical constituents of JEAE were further identified using UPLC-MS/MS, and the molecular network of the JEAE fraction was analyzed. Compounds were isolated through column chromatography, and their antioxidant and hepatoprotective effects were assessed in an H₂O₂-induced HepG2 cell model using molecular assays. Additionally, binding interactions between active compounds and Keap1 were evaluated using molecular docking, molecular dynamics simulations, and surface plasmon resonance.

The ethyl acetate fraction of Desmodium heterocarpon (JEAE) showed remarkable antioxidant activity, with the highest flavonoid contents among extract fractions. In CCl₄-induced liver injury models, JEAE improved liver function, reduced ALT and AST levels, and enhanced antioxidant enzyme activities, suggesting hepatoprotective effects via the Keap1/Nrf2 pathway. 47 compounds were identified in JEAE, and fourteen flavonoids, including two novel compounds (1 and 2), were isolated from the JEAE fraction. Compounds 1, 3, 5, 8, and 14 notably protected HepG2 cells from oxidative damage, reduced ROS levels, and maintained mitochondrial function. These compounds also showed strong binding affinities to Keap1 and other antioxidant receptors, with molecular dynamics simulations confirming their stability and binding potential as effective hepatoprotective agents.

This study demonstrates that the ethyl acetate fraction of Desmodium heterocarpon (JEAE) exhibits significant hepatoprotective effects, largely attributed to its flavonoid-rich composition. The protective effects are mediated through antioxidant pathways, particularly the Keap1/Nrf2 signaling pathway. Newly identified isoflavanes and other flavonoids in JEAE show strong potential as bioactive compounds, with stability and binding affinities supporting their role in reducing oxidative stress. These findings suggest D. heterocarpon as a promising source of hepatoprotective agents and provide a foundation for further exploration of its therapeutic applications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver-related morbidity, cardiovascular disease, and metabolic complications. Lifestyle interventions, including diet and exercise, are first line in treating MASLD. Dietary approaches such as the low-glycemic-index Mediterranean diet, the ketogenic diet, intermittent fasting, and high fiber diets have demonstrated potential in addressing the metabolic dysfunction underlying this condition. The development and progression of MASLD are closely associated with taxonomic shifts in gut microbial communities, a relationship well-documented in the literature. Given the importance of diet as a primary treatment for MASLD, it is important to understand how gut microbiota and their metabolic byproducts mediate favorable outcomes induced by healthy dietary patterns. Conversely, microbiota changes conferred by unhealthy dietary patterns such as the Western diet may induce dysbiosis and influence steatotic liver disease through promoting hepatic inflammation, up-regulating lipogenesis, dysregulating bile acid metabolism, increasing insulin resistance, and causing oxidative damage in hepatocytes. Although emerging evidence has identified links between diet, microbiota, and development of MASLD, significant gaps remain in understanding specific microbial roles, metabolite pathways, host interactions, and causal relationships. Therefore, this review aims to provide mechanistic insights into the role of microbiota-mediated processes through the analysis of both healthy and unhealthy dietary patterns and their contribution to MASLD pathophysiology. By better elucidating the interplay between dietary nutrients, microbiota-mediated processes, and the onset and progression of steatotic liver disease, this work aims to identify new opportunities for targeted dietary interventions to treat MASLD efficiently.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a typical hepatic steatosis with metabolic dysfunction. The composite dietary antioxidant index (CDAI) measures individual antioxidant capacity, and the relationship with MAFLD has received little attention. Our goal is to explore the association of CDAI with MAFLD.

Participants were selected from the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2020. CDAI was calculated basing on six dietary antioxidants, including zinc, selenium, carotenoids, and vitamins A, C, and E. Univariate regression and multivariable logistic regression analysis were conducted to evaluate the correlation between CDAI and MAFLD. We performed subgroup analysis to study the correlation in various populations.

A total of 18,163 participants, including 13,969 MAFLD and 4,194 non-MAFLD, were included. CDAI was significantly negatively correlated with MAFLD. After adjusting for all confounders (including age, gender, race, marital status, poverty ratio, education level, drinking status, smoking status, and physical activity), individuals in the highest quartile of CDAI exhibited a 27% lower likelihood of developing MAFLD than those in the lowest quartile (OR = 0.73; 95% CI [0.66, 0.81], p < 0.001). Physical activity subgroup analysis showed that this negative association was significant in the moderate-intensity physical exercise population (Model 3 in Q4, OR = 0.72; 95% CI [0.58-0.89], p < 0.001). Additionally, the changes in vitamins C were independently associated with MAFLD (Model 3, OR = 0.90; 95% CI [0.86-0.93], p < 0.001).

We found a negative relationship between higher CDAI scores and MAFLD. This study provided a new reference for exploring dietary interventions that affect MAFLD to reduce its incidence.

Research has indicated that treatment with rosuvastatin can improve liver pathology in metabolic-associated fatty liver disease (MAFLD) patients and that treatment with Bifidobacterium can improve MAFLD. Therefore, the effects of Bifidobacterium, rosuvastatin, and their combination on related indices in a rat model of diet-induced MAFLD need to be investigated.

Forty rats were divided into five groups: the normal diet group (N), high-fat diet (HFD) model group (M), HFD + probiotic group (P), HFD + statin group (S), and HFD + probiotic + statin group (P-S). To establish the MAFLD model, the rats in Groups M, P, S, and P-S were fed a HFD for 8 weeks. The treatments included saline in Group N and either Bifidobacterium, rosuvastatin, or their combination in Groups P, S, and P-S by intragastrical gavage. After 4 weeks of intervention, the rats were euthanized, and samples were harvested to analyze gastrointestinal motility and liver function, pathological changes, inflammatory cytokine production, and the expression of proteins in key signaling pathways.

HFD feeding significantly increased the body weight, liver index, and insulin resistance (IR) index of the rats, indicating that the MAFLD model was successfully induced. Bifidobacterium reduced the liver of MAFLD rats, while Bifidobacterium with Rosuvastatin decreased the liver index, IR index, and levels of aspartate aminotransferase and alanine aminotransferase in MAFLD rats. The MAFLD model showed altered expression of proteins in signaling pathways that regulate inflammation, increased production of inflammatory cytokines, an elevated MAFLD activity score (MAS), and pathological changes in the liver. The MAFLD model also showed reduced relative counts of intestinal neurons and enteric glial cells (EGCs), altered secretion of gastrointestinal hormones, and slowed gastrointestinal emptying. Bifidobacterium, rosuvastatin, or their combination inhibited these various changes. HFD feeding changed the rats' gut microbiota, and the tested treatments inhibited these changes. These results suggest that the gastrointestinal motility disorder and abnormal liver function in MAFLD rats may be related to a reduction in Escherichia-Shigella bacteria and an increase in Asticcacaulis bacteria in the gut microbiota and that the improvement in liver function induced by Bifidobacterium plus rosuvastatin may be related to increases in Sphingomonas and Odoribacter bacteria and a decrease in Turicibacter bacteria in the gut microbiota.

The combined use of Bifidobacterium and rosuvastatin could better regulate the gut microbiota of MAFLD model rats, promote gastrointestinal emptying, and improve liver pathology and function than single treatment with Bifidobacterium or rosuvastatin. This provides a better strategy for the treatment of MAFLD.

Oxidative stress has been described as one of the main drivers of intracellular damage and metabolic disorders leading to metabolic syndrome, a major health problem worldwide. In particular, free radicals alter lipid metabolism and promote lipid accumulation in the liver, existing in the hepatic facet of metabolic syndrome, the metabolic dysfunction-associated steatotic liver disease (MASLD). Recent literature has highlighted how nicotine, especially if associated with a high-fat diet, exerts a negative effect on the induction and progression of MASLD by upregulating inflammation and increasing oxidative stress, abdominal fat lipolysis, and hepatic lipogenesis. Moreover, considerable evidence shows the central role of intestinal dysbiosis in the pathogenesis of MASLD and the impact of nicotine-induced oxidative stress on the gut microbiome. This results in an intricate network in which oxidative stress stands at the intersection point between gut microbiome, nicotine, and MASLD. The aim of this review is to delve into the molecular mechanisms linking tobacco smoking and MASLD, focusing on nicotine-induced microbiota modifications and their impact on MASLD development.

Lipid accumulation and oxidative stress, which could be improved by autophagy, are the "hits" of metabolic-associated fatty liver disease (MAFLD). Ganoderma lucidum spore powder (GLSP) has the effect of improving liver function. However, there are few reports about its effects on and mechanisms impacting MAFLD alleviation. This study investigated the effect of GLSP on hepatic lipid accumulation and oxidative stress and explored the role that autophagy played in this effect. The results showed that GLSP effectively reduced lipid accumulation and activated autophagy in the livers of mice with high-fat-diet-induced disease and palmitic acid-induced hepatocytes. GLSP reduced the lipid accumulation by reducing lipogenesis and promoting lipid oxidation in HepG2 cells. It decreased the production of ROS, increased the activity of SOD and CAT, and improved the mitochondrial membrane potential via the Keap1/Nrf2 pathway. The alleviating effects of GLSP on the lipid accumulation and oxidative stress was reversed by 3-methyladenine (3-MA), an autophagy inhibitor. GLSP activated autophagy via the AMPK pathway in HepG2 cells. In conclusion, GLSP could attenuate MAFLD by the improvement of lipid accumulation and oxidative stress via autophagy. This paper is the first to report the improvement of MAFLD through autophagy promotion. It will shed novel light on the discovery of therapeutic strategies targeting autophagy for MAFLD.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disorder in Western countries, encompassing a range of conditions from steatosis to Metabolic Dysfunction-Associated Steatohepatitis (MASH), which can potentially progress to cirrhosis. Lipidomics approaches have revealed significant alterations in the hepatic lipidome associated with both steatosis and steatohepatitis, with these changes correlating with disease manifestation. While the transition from steatosis to MASH remains poorly understood, recent research indicates that both the quantity and quality of deposited lipids play a pivotal role in MASLD progression. In our study, we utilized untargeted and targeted analyses to identify intact lipids and fatty acids in liver biopsies from healthy controls and MASLD patients, categorized based on their histological findings. In total, 447 lipid species were identified, with 215 subjected to further statistical analysis. Univariate and multivariate analyses revealed alterations in triglyceride species and fatty acids, including FA 16:0, FA 16:1, FA 18:3 n6, the sum of MUFA, and the Δ9-desaturase activity ratio. This research provides insights into the connection between dysregulated lipid metabolism in the progression of MASLD, supporting previous findings. Further studies on lipid metabolism could improve risk assessment methods, particularly given the current limited understanding of the transition from steatosis to MASH.

Previous research has investigated the hepatotoxicity of single metal exposure. However, there is limited evidence about metal mixture and their association with metabolic dysfunction-associated fatty liver disease (MAFLD), particularly in the Chinese population.

To investigate the individual and combine effects of 20 metals on MAFLD in a large population in China.

This study included 3651 participants from the Medical Physical Examination Center of Tongji Hospital, Wuhan, China. MAFLD was identified based on ultrasonic graphic evidence of hepatic steatosis and the presence of overweight/obese, diabetes mellitus, or metabolic dysregulation. Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine urinary concentrations of 20 metals. Logistic regression was used to assess the relationship between individual metal and MAFLD, with results presented as odds ratios (ORs) and 95 % confidence intervals (CIs). Weighted quantile sum (WQS) regression was performed to evaluate the combine effect of metals.

The prevalence of MAFLD among the participants was 32.1 % (1173/3651). In singe-metal analysis, high exposure to zinc (OR =1.42; 95 % CI = 1.27, 1.59) and selenium (OR = 1.23; 95 % CI = 1.10, 1.39) were positively associated with MAFLD. No significant association was found for other metals. WQS regression analysis showed that urinary metal mixture was positively associated with MAFLD (OR = 1.32, 95 % CI: 1.15, 1.51), with zinc (50.4 %) being the largest contributor, followed by barium (10.8 %).

In conclusion, our finding suggested that exposure to the mixture of metals was positively correlated with MAFLD, with zinc being the major contributor.

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer related deaths globally. Despite advancements in treatment, drug resistance and adverse side effects have spurred the search for novel therapeutic strategies. This study aimed to investigate how the Emblica officinalis can inhibit key targets involved in HCC progression. Screening of the reported compounds based on ADMET profile and identification of protein targets was done using the literature survey. Protein targets were divided into four major categories including inflammatory, angiogenic, anti-apoptotic as well as proliferative targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to reveal the functional roles of genes. The STRING database was used to analyze the protein-protein interactions (PPI) of target genes. Docking was employed to predict the binding affinity of compounds with target proteins. Subsequently, MD simulation was conducted to assess the stability and dynamics of protein-ligand complexes. A total of 22 active compounds with 25 protein targets have been identified. These targets have a major role in controlling biological processes such as apoptosis, signaling and cellular interactions. KEGG pathway analysis showed that cancer, atherosclerosis, PI3K-Akt, EGFR tyrosine kinase inhibitor resistance and MAPK signaling pathways are mainly involved. Molecular docking by Mcule platform demonstrated that emblicanin A, punigluconin, penta-o-galloylglucose and quercetin showed higher binding energy affinities with BCL2, BCL2L1, c-Met, HSP70, EGFR, FGFR1, PTGS2 and TNFα. MD simulation revealed conformational changes, flexibility, interactions and compactness of protein-ligand complex. The stable protein binding interactions suggest the potential of compounds to inhibit the functions of target proteins. These results suggest that compounds derived from E. officinalis may have the therapeutic potential for treating HCC. See also the graphical abstract(Fig. 1).

Oxidative stress and inflammation are widely recognised as factors that can initiate and facilitate the development of MAFLD. The aim of this study is to analyse the effect of low and high doses of Opuntia stricta var. dillenii peel extract (L-OD and H-OD, respectively) and Opuntia ficus-indica var. colorada pulp extract (L-OFI and H-OFI, respectively), which are rich in betalains and phenolic compounds, on oxidative stress, inflammation, DNA damage and apoptosis in rat livers with diet-induced steatosis. Steatotic diet led to increased final body and liver weight, serum transaminases, hepatic TG content, oxidative status and cell death. H-OFI treatment decreased serum AST levels, while L-OFI reduced hepatic TG accumulation. Oxidative stress was partially prevented with H-OD and H-OFI supplementation, and pro-inflammatory cytokines levels were especially improved with H-OFI treatment. Moreover, H-OFI appears to prevent DNA damage markers. Finally, H-OD and L-OFI supplementation down-regulated the apoptotic pathway. In conclusion, both H-OD and H-OFI supplementation were effective in regulating the progression to metabolic steatohepatitis, triggering different mechanisms of action.

Modified Suanmei-Tang (MST) comprises four plants common to both traditional Chinese medicine and culinary applications, and it can potentially alleviate metabolic-associated fatty liver disease (MAFLD) triggered by a high-fat diet (HFD).

This research aims to investigate the impact and underlying mechanisms of MST in ameliorating MAFLD caused by an HFD.

UHPLC-Q-Orbitrap-MS/MS was used to determine the constituents of MST and to evaluate its effects on MAFLD mouse models. Transcriptomics, network pharmacology, and bioinformatics analysis (including Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis) were utilized to further clarify the mechanisms by which MST acts on MAFLD. The experimental methods included ELISA, real time quantitative PCR (RT-qPCR), Western blot, immunohistochemistry, molecular docking, and metabolomics. Transcriptomics was integrated with metabolomics to find correlations between differentially expressed genes and metabolites, and crucial genes were validated through RT-qPCR.

A total of 23 components of MST were identified. The formulation was found to alleviate metabolic disorders, obesity, insulin resistance, inflammation, and oxidative stress in mice with MAFLD. The findings indicate that MST promoted autophagy by suppressing phosphorylation in the PI3K/AKT/mTOR pathway and enhancing lipid management in the livers of MAFLD mice.

MST could effectively improve lipid metabolism disorders and liver lipid deposition in MAFLD mice, and its mechanism might be related to regulating the PI3K/AKT/mTOR pathway to improve autophagy.

The oral microbiota is the second largest microbiota in the human body and has a significant impact on human health. Recent evidence suggests that dysbiosis of the oral microbiota may be associated with the development of metabolism-associated fatty liver disease (MAFLD). This review aimed to validate the relationship between oral microbial diversity and the development of MAFLD.

A systematic evaluation was performed based on PRISMA guidelines. Three independent reviewers searched for relevant literature in several databases, including PubMed/Medline, Web of Science, and Scopus, with a search date ranging from the establishment of the databases to June 2024.

A total of 1278 publications were initially screened, including five cross-sectional studies, seven case-control studies, one cohort study, and one retrospective study. These studies included a total of 3335 patients with MAFLD, 254 patients with MASH, and 105 patients with liver cirrhosis. All 14 included studies concluded that there was a correlation or potential correlation between oral microbiota and MAFLD. Seven studies found that the composition of the oral microbiota in MAFLD patients differed from that of healthy controls, and specific oral bacteria may be associated with an increased incidence of MAFLD. At the phylum level, several studies found differences in the abundance of the phyla Firmicutes, Proteobacteria, and Clostridia compared to healthy controls. Additionally, a study on oral fungi found significant differences in the phyla Proteobacteria and in the genus Staphylococcus between patients with MAFLD and healthy controls. At the genus level, Porphyromonas was studied most frequently, with all 8 studies identifying infection with Porphyromonas as a significant risk factor for pathological progression in MAFLD. Furthermore, a dysbiosis in the ratio of Porphyromonas gingivalis./Porphyromonas anomalies may be an important marker of MAFLD progression.

There is an important association between the diversity of oral microbiota composition and MAFLD. This finding suggests the importance of oral health assessment and monitoring for the prevention or intervention of MAFLD.

Metabolic-associated steatotic liver disease (MASLD), known as non-alcoholic fatty liver disease (NAFLD) in the past, encompasses a range of liver pathological conditions marked by the excessive lipid accumulation. Consumption of coffee is closely associated with the reduced risk of MASLD. Caffeic acid (CA), a key active ingredient in coffee, exhibits notable hepatoprotective properties. This study aims to investigate the improvement of CA on MASLD and the engaged mechanism. Mice underwent a 12-week high-fat diet (HFD) regimen to induce MASLD, and liver pathology was assessed using hematoxylin-eosin (H&E) and oil red O (ORO) staining. Hepatic inflammation was evaluated by F4/80 and Ly6G immunohistochemistry (IHC) and myeloperoxidase (MPO) measurement. Pathways and transcription factors relevant to MASLD were analyzed by using microarray data from patients' livers. Oxidative damage was evaluated by detecting reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD). Co-immunoprecipitation (CoIP), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) were used to validate the binding between CA and its target protein. CA significantly alleviated liver damage, steatosis and inflammatory injury, and reduced the elevated NAFLD activity score (NAS) in HFD-fed mice. Clinical data indicate that fatty acid metabolism and ROS generation are pivotal in MASLD progression. CA increased the expression of fibroblast growth factor 21 (FGF21), FGF receptor 1 (FGFR1) and β-Klotho (KLB), and promoted fatty acid consumption. Additionally, CA mitigated oxidative stress injury and activated nuclear factor erythroid 2-related factor-2 (Nrf2). In primary hepatocytes isolated from Nrf2 knockout mice, CA's promotion on FGF21 release and inhibition on oxidative stress and lipotoxicity was disappeared. CA could directly bind to kelch-like ECH-associated protein 1 (Keap1) that is an Nrf2 inhibitor protein. This study suggests that CA alleviates MASLD by reducing hepatic lipid accumulation, lipotoxicity and oxidative damage through activating Nrf2 via binding to Keap1.

Metabolic-Associated Fatty Liver Disease (MAFLD) is a clinical-pathological scenario that occurs due to the accumulation of triglycerides in hepatocytes which is considered a significant cause of liver conditions and contributes to an increased risk of death worldwide. Even though the possible causes of MAFLD can involve the interaction of genetics, hormones, and nutrition, lifestyle (diet and sedentary lifestyle) is the most influential factor in developing this condition. Polyphenols comprise many natural chemical compounds that can be helpful in managing metabolic diseases. Therefore, the aim of this review was to investigate the impact of oxidative stress, inflammation, mitochondrial dysfunction, and the role of polyphenols in managing MAFLD. Some polyphenols can reverse part of the liver damage related to inflammation, oxidative stress, or mitochondrial dysfunction, and among them are anthocyanin, baicalin, catechin, curcumin, chlorogenic acid, didymin, epigallocatechin-3-gallate, luteolin, mangiferin, puerarin, punicalagin, resveratrol, and silymarin. These compounds have actions in reducing plasma liver enzymes, body mass index, waist circumference, adipose visceral indices, lipids, glycated hemoglobin, insulin resistance, and the HOMA index. They also reduce nuclear factor-KB (NF-KB), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), blood pressure, liver fat content, steatosis index, and fibrosis. On the other hand, they can improve HDL-c, adiponectin levels, and fibrogenesis markers. These results show that polyphenols are promising in the prevention and treatment of MAFLD.