Liver fibrosis is a passive and irreversible wound healing process caused by chronic liver injury. Research has shown that the upregulation of hypoxia inducible factor-1 alpha (HIF-1α) is closely related to the occurrence and development of liver fibrosis and HIF-1 α may be a promising target for the treatment of liver fibrosis. AMSP-30 m is a newly developed novel HIF-1α inhibitor by our group, which has strong anti-tumor and anti-inflammatory effects. In this study, we described the therapeutic effect and specific mechanism of AMSP-30 m on carbon tetrachloride (CCl4) induced liver fibrosis in mice. Liver fibrosis induced by CCl4 in mice and liver fibrosis induced by cobalt dichloride (CoCl2) in LX-2 cells (human hepatic stellate cell (HSC) line) were studied. Hematoxylin & eosin (H&E)and Masson's trichrome staining were used to observe pathological conditions. Western Blot, immunofluorescence and immunohistochemistry were used to detect protein expression and localization in cells, and quantitative real-time PCR analysis (qRT-PCR) was used to detect mRNA expression. Biochemical detection kits were used to detect alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. The results demonstrated that AMSP-30 m significantly alleviated pathological symptoms, reduced ALT and AST levels, and inhibited the expression of alpha-smooth muscle actin (α-SMA) and collagen type I (COL1α1) in CCl4-induced liver fibrosis in mice. AMSP-30 m could significantly reduce the expression of HIF-1α and sonic hedgehog (Shh) pathway related proteins (Smoothened (Smo), Shh, and glioma-associated oncogene-1 (Gli-1)) in CCl4 induced liver fibrosis mice. AMSP-30 m also played a similar role in the CoCl2-induced anoxic liver fibrosis model of LX-2 cells. Further experiments showed that Cyclopamine (a Shh inhibitor) could significantly inhibit the increase of α-SMA and COL1α1 resulting from HIF-1α but not significantly inhibit HIF-1α induced by CoCl2 in LX-2 cells. And the combination of Cyclopamine and AMSP-30 m further reduced the expression of α-SMA and COL1α1 induced by HIF-1α. In summary, this study demonstrates that the HIF-1α inhibitor AMSP-30 m exerts a robust anti-fibrotic effect by inhibiting the Shh pathway, which is identified as a critical underlying mechanism. These findings suggest a promising therapeutic strategy for the treatment of liver fibrosis.

Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses a spectrum of liver diseases ranging from metabolic dysfunction-associated fatty liver to metabolic dysfunction-associated steatohepatitis, which may progress to liver cirrhosis and hepatocellular carcinoma. Several mechanisms, including obesity, insulin resistance, dyslipidemia, inflammation, apoptosis, mitochondrial dysfunction, and reactive oxygen species, have been proposed to underlie the progression of MAFLD. Transcription factors are proteins that specifically bind to DNA sequences to regulate the transcription of target genes. Numerous transcription factors regulate MAFLD by modulating the transcription of genes involved in steatosis, inflammation, apoptosis, and fibrosis. Here, we review the pathological factors associated with MAFLD, with a particular emphasis on the transcription factors that contribute to the progression of MAFLD and their therapeutic implications.

The pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) involves multiple pathophysiological processes, including abnormal lipid metabolism, insulin resistance, oxidative stress, endoplasmic reticulum stress, inflammatory response, and fibrosis. These factors interact to form a complex network and the development of synergistic and pleiotropic drug modalities targeting multiple pathogenesis of MASH may have a better therapeutic effect. Herein, the bifunctional proteolytic targeting chimeras (PROTAC) technology was utilized for developing pleiotropic drugs for MASH treatment. We constructed a Keap1-recruiting degrader KB-3 which stabilizes the natural Keap1 target Nrf2 and degrades BRD4 synergistically, exhibiting combined therapeutic advantages against MASH-related pathologies. Experimental results confirmed that KB-3 could effectively alleviate MASH in mice by improving lipid metabolic disorder, enhancing the defense against oxidative stress, reducing inflammation, and delaying the progression of liver fibrosis. Such Keap1-recruiting degrader offering a single-molecular approach with polypharmacology effects may be an attractive strategy for the treatment of multifactorial disease.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of Cd36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.

To characterise patients with metabolic dysfunction-associated steatohepatitis (MASH) in England and to estimate its associated healthcare resource use (HCRU) and costs, both overall and by progression status and comorbidities.

This was a retrospective observational study of adults with a MASH-coded primary and/or secondary care recorded diagnosis in England (2011-2020). The analysis used data from the Clinical Practice Research Datalink linked to the Hospital Episode Statistics and death registrations. Annualised all-cause and MASH-related (ie, coded as MASH, end-stage liver disease or major adverse cardiovascular event) HCRU and costs were calculated for patients with incident MASH. Subgroup analyses were conducted for patients with type 2 diabetes, overweight/obesity, cardiovascular disease or progression to cirrhosis. Comparative cost analysis was conducted between those with progressed MASH and those who did not progress.

A total of 2696 patients were included (mean follow-up: 4 years). Incidence of MASH was estimated at 4.7 per 100 000 person-years overall and increased among patients with key comorbidities. Patients who had type 2 diabetes had greater HCRU and costs than those who did not (eg, mean 1.8 vs 1.0 all-cause inpatient admissions and £2227 vs £1151 all-cause inpatient costs per-patient per-year). Some patients with MASH progressed to compensated (8.6%) or decompensated cirrhosis (6.5%) during the study. HCRU and costs were substantially higher among patients who progressed than among those who did not (eg, mean 2.4 vs 1.1 all-cause inpatient admissions and £3620 vs £1290 all-cause inpatient costs per-patient per-year).

HCRU and costs associated with MASH are higher among patients who have cardiometabolic comorbidities or who progress to advanced disease stages. Therefore, efforts to detect cases early and prevent disease progression could reduce healthcare burden.

BACKGROUNDAlterations in circulating metabolites have been described in obese metabolic dysfunction-associated steatotic liver disease (MASLD), but data on lean MASLD are lacking. We investigated serum metabolites, including microbial bile acids and short-chain fatty acids (SCFAs), and their association with lean and obese MASLD.METHODSSerum samples from 204 people of European descent were allocated to groups: lean healthy, lean MASLD, obese healthy, and obese MASLD (n = 47). Liquid chromatography-mass spectrometry-based metabolomics and linear model analysis were performed. MASLD prediction was assessed based on least absolute shrinkage and selection operator regression. Functional effects of altered molecules were verified in organotypic 3D primary human liver cultures.RESULTSLean MASLD was characterized by elevated isobutyrate, methionine sulfoxide, propionate, and phosphatidylcholines. Patients with obese MASLD had increased sarcosine and decreased lysine and asymmetric dimethylarginine. Using metabolites, sex, and BMI, MASLD versus healthy could be predicted with a median AUC of 86.5% and 85.6% in the lean and obese subgroups, respectively. Functional experiments in organotypic 3D primary human liver cultures showed propionate and isobutyrate induced lipid accumulation and altered expression of genes involved in lipid and glucose metabolism.CONCLUSIONLean MASLD is characterized by a distinct metabolite pattern related to amino acid metabolism, lipids, and SCFAs, while metabolic pathways of lipid accumulation are differentially activated by microbial metabolites. We highlight an important role of microbial metabolites in MASLD, with implications for predictive and mechanistic assessment of liver disease across weight categories.FUNDINGRobert Bosch Stiftung, Swedish Research Council (2021-02801, 2023-03015, 2024-03401), ERC Consolidator Grant 3DMASH (101170408), Ruth and Richard Julin Foundation for Gastroenterology (2021-00158), SciLifeLab and Wallenberg National Program for Data-Driven Life Science (WASPDDLS22:006), Novo Nordisk Foundation (NNF23OC0085944, NNF23OC0084420), PMU-FFF (E-18/28/148-FEL).

Metabolic steatohepatitis (MASH) is a common liver disease, and its association with serum thyroid hormone levels is unclear. This study aimed to analyze the association between MASH and serum levels of thyroid hormones in patients with normal thyroid function.

638 non-alcoholic fatty liver disease patients hospitalized in our hospital from March 2021 to March 2024 were retrospectively selected and divided into MASH (n = 262) and non-MASH (n = 376) groups based on the diagnosis made by expert pathologists. The clinical data of the patients were collected, and multivariate logistic regression analysis was utilized to investigate the association between MASH and serum thyroid hormone levels.

Serum levels of thyroid-stimulating hormone (TSH) and free triiodothyronine (FT3) in the MASH group were significantly higher compared to the non-MASH group, and serum free thyroxine (FT4) levels were lower than those in non-MASH group. The FT3/FT4 ratio in MASH group was higher than that in non-MASH group (P < 0.05). Logistic regression analysis showed that serum levels of TSH, FT3 and FT4 were independent influencing factors for MASH. The area under receiver operating characteristic (ROC) curve of TSH, FT3, FT4 and FT3/FT4 for predicting the occurrence of MASH were 0.944, 0.973, 0.753 and 0.959, respectively.

Elevated serum levels of TSH, FT3, and the FT3/FT4 ratio, along with decreased serum FT4 levels, were independently associated with an increased risk of MASH.

Metabolic-dysfunction associated steatotic liver disease (MASLD) is associated with prevalent cardiovascular disease. More favorable cardiovascular health (CVH) profiles are associated with a lower prevalence of MASLD in cross-sectional studies. The relationship between long-term CVH patterns and MASLD prevalence in midlife remains unknown.

Participants (aged 18-30 years at baseline) of the CARDIA (Coronary Artery Risk Development in Young Adults) study who had individual CVH components measured at 7 examinations over 20 years and liver fat assessed by noncontrast computed tomography at year 25 follow-up were included. CVH score was defined using published American Heart Association definitions. Group-based trajectory modeling was used to identify CVH trajectories. MASLD was defined as liver attenuation of ≤51 Hounsfield units with at least 1 metabolic risk factor after excluding other causes of liver fat. Logistic regression was used to examine associations of CVH trajectory groups and MASLD prevalence. At baseline, 39% of 2529 participants had high and 5% had low CVH, respectively. MASLD prevalence at year 25 was 23% (n=587). Five distinct CVH trajectories were identified. Between the 2 groups that started at similar CVH scores, those whose CVH declined over time had a higher prevalence of MASLD at year 25 (7.0% in high-stable versus 23.0% high-decreasing; 24.4% in moderate-stable versus 35.7% in moderate-decreasing). Lower and decreasing trajectories were associated with higher year-25 MASLD prevalence compared with the high-stable trajectory.

Achieving and maintaining high CVH scores starting in young adulthood lowers the risk of prevalent MASLD in midlife.

The novel serum high-sensitivity C-reactive protein-triglyceride glucose index (CTI) has been recognized as an optimal parameter encompassing both insulin resistance (IR) and inflammation, which are potential mechanisms contributing to non-alcoholic fatty liver disease (NAFLD). This study aims to examine the correlation between CTI and NAFLD/liver fibrosis in American adults.

This is a cross-sectional study utilizing data from NHANES during the period from 2017 to 2020. The composite CTI was calculated through the formula: 0.412×Ln [(high-sensitivity C-reactive protein(hs-CRP)] + Ln(triglycerides × fasting plasma glucose/2). To explore the correlation between CTI and NAFLD/liver fibrosis, multivariate logistic regression analyses, subgroup analyses, restricted cubic spline (RCS) regression, and receiver operating characteristic (ROC) analysis were employed.

Among 3,488 participants, 42.7% (n = 1,488) were diagnosed as NAFLD, while 9.4% (n = 329) exhibited liver fibrosis. Logistic regression and RCS regression analyses demonstrated a significant positive linear correlation between CTI and the prevalence of NAFLD (OR = 1.94, 95% CI: 1.70, 2.22) as well as liver fibrosis (OR = 1.38, 95% CI: 1.14, 1.67), even after being adjusted for potential confounding variables. Furthermore, a significant correlation between CTI and the prevalence of NAFLD/liver fibrosis was observed across various subgroups. ROC analysis revealed that CTI can serve as a more robust identify for the prevalence of NAFLD (AUC = 0.756) and liver fibrosis (AUC = 0.702) compared to triglyceride glucose index (TyG) and hs-CRP alone.

Elevated levels of CTI are directly associated with significant liver fibrosis and the presence of NAFLD, indicating its potential utility as a biomarker for liver fibrosis and NAFLD.

Microplastics (MPs) pose emerging threats to human health, with growing concerns about liver toxicity and other harmful effects from plastic particles. While aquatic species exhibit hepatic vulnerability to micro/nanoplastics, the role of submicroplastics (100 nm-1 μm) in mammalian non-alcoholic fatty liver disease (NAFLD) progression remains unclear. We investigated the effects of a 12-week exposure to 0.5 μm polystyrene MPs (submicroplastics) in drinking water, administering this to ApoE-deficient mice fed either a chow diet (CD) or a Western diet (WD). Submicroplastics accumulated predominantly in the liver and were excreted in the feces. Histologically, submicroplastics significantly increased NAFLD activity scores, hepatic steatosis (Oil Red O-positive area), and fibrosis (Masson-positive area), with maximal severity in the WD+MPs group. Also, the MPs exposure group had increases in positive areas for F4/80 and inflammatory markers TNF-α, IL-1β and IL-6 expression under both diets. Concurrently, submicroplastics inhibited antioxidant defenses by lowering levels of superoxide dismutase and glutathione, while also increasing the lipid peroxidation marker malondialdehyde. WD-fed mice exhibited pronounced MPs-induced lipid dysregulation, including elevated hepatic triglycerides, total cholesterol, and free fatty acids (FAs). Mechanistically, submicroplastics upregulated FA synthesis regulators (ACC, FASN, SREBP1) while downregulating FA oxidation mediators (CPT1A, ACOX1, PPARα) in the livers under a WD. Our findings demonstrate that chronic submicroplastics-exposure exacerbates the progression of NAFLD in ApoE-deficient mice by disturbing lipid metabolism, enhancing oxidative stress, and amplifying inflammatory responses. This study provides experimental evidence linking environmental plastic pollution to accelerated metabolic liver disease, thereby highlighting the urgent need for plastic exposure control strategies.

This study examines the effects of continuous versus interrupted lifelong exercise on lipid metabolism in naturally aging male BALB/c mice. Five-week-old male BALB/c mice were randomly assigned to five groups: young control group (YC), natural ageing control group (AC), exercise cessation group (DE), middle-aged commencing exercise group (ME), and lifelong exercise group (LE). Moderate Intensity Continuous Training exercise sessions were conducted three times per week, with each session lasting 50 min; after exercise interventions until 72 weeks of age, the following parameters were measured: body morphology, exercise capacity, blood lipid, liver fat content, liver function, expression of liver lipid metabolism-related genes and endoplasmic reticulum stress-related genes, and activities of liver metabolism enzymes. The results suggest that advancing age leads to disrupted lipid processing, reduced hepatic performance, and increased endoplasmic reticular tension. Compared with the AC group, the ME and LE cohorts showed reduced serum lipids, whereas the LE group exhibited elevated high-density lipoprotein cholesterol (HDL-C) levels (P < 0.05). Post-exercise reductions were observed in hepatic total cholesterol and free fatty acid (FFA). Moreover, the exercises mitigated age-related hepatic impairments and diminished susceptibility towards cirrhosis despite higher aspartate aminotransferase (AST) and lower albumin (ALB) levels being evident within the DE cohort (P < 0.05). Exercise demonstrates the potential to mitigate age-related abnormalities in lipid metabolism. Middle-aged commencing and lifelong exercise interventions are more effective in alleviating lipid abnormalities than exercise cessation in middle age. This disparity in efficacy can be attributed to differences in regulating endoplasmic reticulum stress, enhancing liver lipid oxidation capacity, and reducing lipid synthesis ability. Notably, middle-aged individuals commencing exercise yield similar outcomes in regulating aging-associated abnormal lipid metabolism compared to the lifelong exercise group. This highlights the importance of initiating exercise in middle age, as it remains beneficial even if lifelong commitment is unfeasible, so exercise initiation in midlife is still beneficial. However, to prevent liver lipid metabolism disorders later in life, the earlier exercise initiation, the better.

Fibrosis is the pathological outcome of many chronic inflammatory diseases, affecting various human organs. It is a significant contributor to global morbidity and mortality that affects nearly half of the elderly population. Pirfenidone (PFD) and nintedanib are approved by the FDA for treating pulmonary fibrosis, but these treatments are associated with poor tolerability and limited efficacy. Moreover, no antifibrotic drugs are approved for other fibrosis-related diseases, highlighting an urgent unmet medical need for more effective therapies. Here we report the in vivo pharmacological activities of AK3280, a novel, orally bioavailable small molecule designed to enhance pharmacokinetics, antifibrotic activity, and tolerability over PFD. AK3280 demonstrated antifibrotic effects across multiple organs, including the lungs, liver, heart, and skin, in various animal models. These results suggest that AK3280 holds promise as a clinically beneficial antifibrotic therapy for a range of fibrotic diseases, especially pulmonary, hepatic, cardiac, and skin fibrosis.

To comprehensively evaluate the therapeutic efficacy of pioglitazone and SGLT2 inhibitors (SGLT2i) in patients with MASLD and Type 2 Diabetes(T2DM).

Electronic databases, including Web of Science, PubMed, the Cochrane Library, China National Knowledge Internet (CNKI), Wan-Fang Digital Database, and China Science and Technology Journal Database (VIP) were searched from inception to December 2024. Two reviewers independently assessed study eligibility, performed continuous data extraction， and independently evaluated bias risks. Liver ultrasonography, computed tomography (CT), and biochemical indices were utilized to determine the impact of treatment in both groups. Improvement in liver biomarkers and fibrosis as primary outcome indicators; Improvement in body composition, metabolic parameters, glucose parameters, and incidence of adverse effects as a secondary outcome indicator. For continuous variables, mean and standard deviation (SD) were extracted. RevMan 5.4 software was used to systematically analyze the literature, including heterogeneity testing, odds ratios (OR) calculation, and 95 % confidence intervals (CI) for each influencing factor.

Nine randomly controlled trials with 755 Asian participants were included. Our research showed that SGLT2i was more effective than pioglitazone in improving fibrosis-4 score (SMD 0.41 [95%CI 0.18,0.64] p = 0.005), visceral fat area (SMD 0.34 [95%CI 0.14,0.54] p = 0.0007), BMI (SMD 0.29 [95%CI 0.03,0.56] p = 0.03), and low-density lipoprotein levels (SMD 0.21 [95%CI 0.04,0.38] p = 0.01). In contrast, no statistically significant differences were observed in other outcomes.

Our study demonstrated that in patients with MASLD and T2DM, SGLT2i was more effective overall in improving liver fibrosis, blood lipids, liver fat, and body composition in the short term. These findings establish a theoretical basis for safe and rational drug use in clinical practice. Additionally, they may contribute to new insights into the pathogenesis of MASLD and type 2 diabetes and drug discovery and development efforts.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated long-term liver benefits in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D). However, no direct comparison between these therapies has been conducted. This study aimed to compare major adverse liver outcomes (MALOs) between GLP-1 RAs and SGLT2is in patients with MASLD and T2D.

Using the TriNetX Research Network, a multinational and multi-institutional database, we identified adults with MASLD and T2D who received their first prescription for either a GLP-1 RA or an SGLT2i between January 2010 and June 2023. We conducted a propensity score-matched (PSM) cohort study comparing new users of GLP-1 RAs and SGLT2is. The primary outcome was the risk of MALOs, a composite endpoint consisting of decompensated cirrhosis events, hepatocellular carcinoma, and liver transplantation. Secondary outcomes included all-cause mortality and individual components of the primary outcome.

This study included 15,176 pairs of patients treated with either a GLP-1 RA or a SGLT2i. The adjusted hazard ratio (HR) for MALO associated with GLP-1 RAs relative to SGLT2is was 0.84 (95% confidence interval [CI]: 0.73-0.97; incidence rate: 88.9 versus 105.3 events per 10,000 person-years), primarily driven by reduction in decompensated cirrhosis events (adjusted HR: 0.83, 95% CI: 0.71-0.96). GLP-1 RAs were associated with lower all-cause mortality (adjusted HR: 0.84, 95% CI: 0.75-0.94).

GLP-1 RAs are associated with better long-term liver outcomes compared to SGLT2is in patients with MASLD and T2D.

Obesity induction in mice requires high-fat diet exposure. Although hepatic steatosis develops, progression to inflammation and fibrosis, as in humans, requires prolonged exposure and additional dietary factors. Immunosuppression at room temperature may slow this progression. We evaluated thermoneutrality's effect on metabolic dysfunction-associated steatohepatitis (MASH) development using a fibrosis-inducing MASH [Gubra-Amylin NASH (GAN)] diet. Mice were fed either a MASH or chow diet and housed at room temperature or thermoneutrality. MASH diet groups were euthanized monthly from 4 to 7 mo. Serum markers of hepatic function were analyzed, and liver histology assessed steatosis, inflammation, ballooning [nonalcoholic fatty liver disease activity score (NAS) score], and fibrosis via Picrosirius Red staining. MASH diet increased body weight, liver-to-body mass ratio, and hepatic fat, with no difference between housing conditions. Housing temperature had minimal effects on MASH. Serum markers and hepatic fibrosis were similar across groups. NAS score was lower at 4 mo in thermoneutral MASH mice but not by 7 mo. Thermoneutrality did not significantly impact MASH development. These findings, alongside existing literature, suggest thermoneutral housing does not consistently enhance MASH progression in GAN MASH-fed mice.NEW & NOTEWORTHY The development of MASH in mice-does housing temperature make a real difference?

The benefits of exercise for metabolic health occur in a dose-dependent manner. However, the adverse effects of overtraining and their underlying mechanisms remain unclear. Here, we show that overtraining induces hepatic fibrosis. Mechanistically, we find that excessive lactate accumulation in skeletal muscle leads to the lactylation of SH3 domain-containing 3 (SORBS3), triggering its liquid-liquid phase separation (LLPS). LLPS of SORBS3 enhances its interaction with flotillin 1 and selectively facilitates the sorting of F-box protein 2 (FBXO2) into small extracellular vesicles, referred to as "lactate bodies." Lactate bodies induce hepatocyte apoptosis followed by hepatic stellate cell activation via myeloid cell leukemia sequence 1 (MCL1)-BAX/BAK signaling. Inhibition of SORBS3 lactylation or FBXO2 disrupts lactate bodies formation and alleviates overtraining-triggered liver fibrosis. Likewise, reduction of muscle lactate bodies formation by salidroside attenuates overtraining-induced liver fibrosis. Collectively, we identify a process by which overtraining induces hepatic fibrosis, highlighting a potential therapeutic target for liver health.

Nucleic acid-based therapeutics have become a key pillar of the 'third wave' of modern medicine, following the eras of small molecule inhibitors and antibody drugs. Their rapid progress is heavily dependent on delivery technologies, with the development of N-acetylgalactosamine (GalNAc) conjugates marking a breakthrough in targeting liver diseases. This technology has gained significant attention for its role in addressing chronic conditions like chronic hepatitis B (CHB) and nonalcoholic steatohepatitis (NASH), which are challenging to treat with conventional methods.

This review explores the origins, mechanisms, and advantages of GalNAc-siRNA delivery systems, highlighting their ability to target hepatocytes via the asialoglycoprotein receptor (ASGPR). The literature reviewed covers preclinical and clinical advancements, particularly in CHB and NASH. Key developments in stabilization chemistry and conjugation technologies are examined, emphasizing their impact on enhancing therapeutic efficacy and patient compliance.

GalNAc-siRNA technology represents a transformative advancement in RNA interference (RNAi) therapies, addressing unmet needs in liver-targeted diseases. While significant progress has been made, challenges remain, including restricted targeting scope and scalability concerns. Continued innovation is expected to expand applications, improve delivery efficiency, and overcome limitations, establishing GalNAc-siRNA as a cornerstone for future nucleic acid-based treatments.

Smoking was identified as a risk factor for the development of liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, the association between smoking cessation history and the development of liver fibrosis remains unclear. This study was intended to analyze the association between smoking cessation history and significant liver fibrosis in adult MASLD participants in the United States.

This study utilized data from 2643 patients with MASLD from the National Health and Nutrition Examination Survey (NHANES). Significant liver fibrosis was detected based on transient elastography measurements. According to the smoking questionnaire data, patients were categorized as non-smokers, ex-smokers and current smokers. A multivariate logistic regression analysis, adjusted for weights, was performed to investigate the relationship between smoking cessation history and the presence of significant liver fibrosis in participants with MASLD.

A total of 2643 patients with MASLD were included in this study. Compared with non-smokers, ex-smokers had a slightly elevated risk of developing significant liver fibrosis (OR: 1.07, 95% CI: 1.02-1.13). Specifically, a positive correlation was observed between patients who quit smoking for < 20 years and significant liver fibrosis (OR: 1.07, 95% CI: 1.01-1.15). Furthermore, MASLD patients who started regularly smoking at an age of ≤ 20 years (OR: 1.09, 95% CI: 1.02-1.16) and had a smoking duration of ≥ 10 years before quitting (OR: 1.10, 95% CI: 1.02-1.18) were also highly correlated with an increased likelihood of developing significant liver fibrosis.

This study revealed that individuals with MASLD who have ceased smoking exhibit an elevated risk for significant liver fibrosis when compared to those who never smoked. It is highly emphasized that MASLD patients who quit smoking for < 20 years, started regularly smoking at an age of ≤ 20 years, and had a smoking duration of ≥ 10 years before quitting should be extremely vigilant regarding the risk of significant liver fibrosis.

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.

The prevalence of nonalcoholic steatohepatitis (NASH) is rising annually, posing health and economic challenges, with limited treatments available. Diosgenin, a natural steroidal compound found in various plants, holds potential as a therapeutic candidate. Recent studies have confirmed diosgenin's anti-inflammatory and metabolism-modulating properties. However, its therapeutic effects on NASH and the underlying mechanisms are still unclear. This study aims to explore diosgenin's protective effects and pharmacological mechanisms against NASH using network pharmacology, molecular docking, and experimental validation. We gathered potential targets of diosgenin and NASH from various databases to generate protein-protein interaction (PPI) networks. GO and KEGG pathway enrichment analyses identified key targets and mechanisms. Molecular docking confirmed the binding capacity between diosgenin and core target proteins. Additionally, a NASH cell model was developed to validate the pharmacological effects of diosgenin. Our investigation identified nine key targets (ALB, AKT1, TP53, VEGFA, MAPK3, EGFR, STAT3, CASP3, IGF1) that interact with diosgenin. Molecular docking indicated potential bindings interactions, while enrichment analyses revealed that diosgenin may enhance fatty acid metabolism via the PI3K-Akt pathway. Cellular experiments confirmed that diosgenin activates this pathway, reduces SCD1 expression, and decreases triglyceride and IL-6 levels. Our study elucidates that diosgenin may ameliorate triglyceride deposition and inflammation through the PI3K-Akt pathway.

Non-alcoholic steatohepatitis (NASH), characterized by severe fatty liver-associated inflammation and hepatocellular damage, is a major precursor to cirrhosis and hepatocellular carcinoma. While the exact pathogenesis of NASH remains unclear, gut microbiota dysbiosis has been implicated as a key factor contributing to endotoxin translocation and chronic liver inflammation. Recent studies have highlighted the therapeutic potential of bovine colostrum-derived extracellular vesicles (BCEVs) in modulating gut microbiota and enhancing gut barrier function, but their effects on NASH remain largely unexplored. To investigate the potential protective effects of BCEVs against NASH, 8-wk-old mice were fed a NASH-inducing diet for 3 wks while concurrently receiving oral BCEV administration. BCEV treatment markedly ameliorated hepatic steatosis, fibrosis, and inflammation. Transcriptomic analyses demonstrated a notable reduction in lipid metabolism, bacterial response, and inflammatory pathways in the intestine, as well as reduced expression of inflammation- and fibrosis-related pathways in the liver. Gut microbiota profiling revealed an increased abundance of Akkermansia, accompanied by enhanced cholesterol excretion. Furthermore, BCEV treatment promoted the production of tight junction proteins and mucin in the gut, reinforcing intestinal barrier integrity. These findings suggest that BCEVs promote the proliferation of Akkermansia, which in turn prevents endotoxin translocation to the liver. This reduction in endotoxin leakage alleviates hepatic inflammation and fibrosis. Overall, this study highlights the therapeutic potential of BCEVs as a novel strategy for managing NASH by targeting the gut-liver axis through the modulation of gut microbiota and barrier function.

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.

Chronic liver disease is defined by persistent harm to the liver that might result in decreased liver function. The two prevalent chronic liver diseases are alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). There is ample evidence that the pathogenesis of these two chronic liver diseases is closely linked to gastrointestinal dysfunctions that alters the gut-liver crosstalk. These alterations are mediated through the imbalances in the gut microbiota composition/function that combined with disruption in the gut barrier integrity allows for harmful gut microbes and their toxins to enter the portal circulation and reach the liver to elicit an inflammatory response. This leads to further recruitment of systemic inflammatory cells, such as neutrophils, T-cells, and monocytes into the liver, which perpetuate additional inflammation and the development of progressive liver damage. Many therapeutic modalities, currently used to prevent, attenuate, or treat chronic liver diseases are aimed at modulating gut dysbiosis and improving intestinal barrier function. Betaine is a choline-derived metabolite and a methyl group donor with antioxidant, anti-inflammatory and osmoprotectant properties. Studies have shown that low betaine levels are associated with higher levels of organ damage. There have been several publications demonstrating the role of betaine supplementation in preventing the development of ALD and MASLD. This review explores the protective effects of betaine through its role as a methyl donor and its capacity to regulate the protective gut microbiota and maintain intestinal barrier integrity to prevent the development of these chronic liver diseases. Further studies are needed to enhance our understanding of its therapeutic potential that could pave the way for targeted interventions in the management of not only chronic liver diseases, but other inflammatory bowel diseases or systemic inflammatory conditions.

Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), involves hepatic lipid accumulation, inflammation, and fibrosis. It can progress to cirrhosis or hepatocellular carcinoma without timely treatment. Current treatment options for MASH are limited. This study explores the therapeutic effects of fluorofenidone (AKF-PD), a novel small-molecule compound with antifibrotic and anti-inflammatory properties, on MASH in mouse model. Mice fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) were treated with AKF-PD, resulting in reduced serum ALT, AST, hepatic lipid accumulation, liver inflammation, and fibrosis. Network pharmacology and RNA-sequencing analyses suggested that AKF-PD influenced multiple metabolic, inflammatory, and fibrosis-related pathways. Further experiments verified that AKF-PD activated hepatic AMPK signaling, leading to the inhibition of the downstream SREBF1/SCD1 pathway and the activation of autophagy. Additionally, AKF-PD suppressed the expression of various inflammatory factors, reduced macrophage infiltration, and inhibited NLRP3 inflammasome activation. Moreover, AKF-PD attenuated liver fibrosis by inhibiting TGFβ1/SMAD signaling. In conclusion, this study reveals that AKF-PD effectively decreases hepatic lipid accumulation, liver inflammation and fibrosis in a CDAHFD-induced MASH model, positioning AKF-PD as a promising candidate for the treatment of MASH.

The aim of this study was to explore the relationship between the hemoglobin glycation index (HGI) of Congestive Heart Failure (CHF) patients and their risk of mortality within 365 days.

The Medical Information Mart for Intensive Care (MIMIC-IV) database supplied the patient data for this study, which was categorized into quartiles based on the HGI. The primary endpoint was all-cause mortality within a 365-day period. Kaplan-Meier (K-M) analysis was utilized to compare this primary endpoint across the four aforementioned groups. The relationship between the HGI and the endpoint was examined using restricted cubic splines (RCS) and a Cox proportional hazards analysis.

A total of 985 patients were included in this study. HGI was significantly associated with 30 days mortality (15.9%; HR, 0.79; 95% CI, (0.67~0.92); P=0.003) and 60 days mortality (19.3%; HR, 0.83; 95% CI, (0.72~0.96); P=0.011) and 90 days mortality (22.1%; HR, 0.86; 95% CI, (0.75~0.99); P=0.031) and 365 days mortality (30.7%; HR, 0.97; 95% CI, (0.86~1.09); P=0.611) in patients with critical CHF in the completely adjusted Cox proportional risk model. RCS analysis revealed a U-shaped relationship between HGI and outcome events. KM curves survival analysis suggests a correlation between 30 days and 365 days mortality in HGI and CHF patients.

A higher HGI has a more protective effect than a low HGI for patients with CHF and was directly associated with short-term mortality rates. These findings may be helpful in the management of patients with CHF.

Nonalcoholic steatohepatitis (NASH) is a significant threat to human health. Our previous study revealed that salidroside attenuated NASH and regulated the gut microbiota. However, whether the therapeutic effect of salidroside depends on gut microbiota remains to be determined. Therefore, we conducted further experiments to elucidate the essential functions of gut microbiota-associated metabolic pathways in the anti-NASH effects of salidroside. Our results showed that salidroside effectively alleviated lipid accumulation and inflammatory injury in NASH mice. 16S rRNA sequencing revealed that salidroside increased the abundance of Bacteroides. Mice receiving fecal microbiota transplantation (FMT) from salidroside-treated also presented less hepatic steatosis and higher abundance of Bacteroides. Antibiotics eliminated the effects of salidroside on hepatic steatosis and the gut microbiota. Mechanistically, salidroside and FMT from salidroside-treated altered the bile acid (BA) profile by decreasing the levels of conjugated BAs and tauro-α/β-muricholic acid and activated downstream farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Furthermore, we found that inhibitors of bile salt hydrolase (BSH) and FXR/TGR5 abolished the effects of salidroside and reduced downstream carnitine palmitoyltransferase 1α and lipoprotein lipase expression. These data demonstrate that salidroside attenuated NASH via gut microbiota-BA-FXR/TGR5 signaling pathway and reveal the underlying mechanism of salidroside on NASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a globally prevalent liver disease, closely linked to the rising incidence of obesity, diabetes, and metabolic syndrome. Dapagliflozin (DaPa), a sodium-glucose cotransporter-2 inhibitor, is primarily prescribed for diabetes management. It has shown potential efficacy in managing MASLD in clinical settings. However, the molecular mechanisms underlying the effects of DaPa on MASLD remain poorly understood. Hence, we aimed to investigate the role of and mechanisms underlying DaPa in MASLD.

Male diet-induced obese (DIO) C57BL/6J mice were injected with streptozotocin (STZ), followed by a high-fat diet regimen to stimulate metabolic dysfunction. Subsequently, they received DaPa via gavage for 5 weeks. Hepatic lipid accumulation, pathological alterations, inflammatory markers, and liver fibrosis were assessed.

DaPa administration reduced liver fat accumulation in DIO mice. Additionally, it decreased oxidative stress and lipid peroxide levels, which was attributed to the upregulation of glutathione and the downregulation of malondialdehyde and reactive oxygen species levels. Notably, DaPa downregulated the inflammatory response and reduced liver fibrosis.

DaPa protects against MASLD by inhibiting lipid accumulation, inflammation, oxidative stress, and liver fibrosis.

Non-alcoholic steatohepatitis (NASH), as a progressive form of Non-alcoholic fatty liver disease (NAFLD), poses a significant threat to human health as a prevalent and common condition, with a lack of safe and effective therapeutic options. However, the therapeutic effects and potential mechanisms of Lang Qing Ata (LQAtta) against NASH remain elusive.

The components of LQAtta were identified using Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS). Subsequently, we employed network construction and analysis approaches within the field of network pharmacology. By integrating known databases and target prediction algorithms, which encompassed database-based target prediction, protein-protein interaction networks, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, we unveiled the potential key targets and signaling pathways that these bioactive components might engage with. These discoveries were further validated in subsequent mouse models. An HFHC-induced NASH mouse model was used to validate the therapeutic effects and potential mechanisms of LQAtta on NASH.

From the UHPLC-MS/MS analysis of LQAtta, a total of 1518 chemical components were identified, with 106 of them being absorbed into the bloodstream. Additionally, based on the acquisition of targets from both LQAtta and the NASH database, a total of 160 common targets were screened. KEGG enrichment analysis indicated that LQAtta may alleviate NASH by modulating pathways such as the Toll-like receptor signaling pathway, the NF-κB signaling pathway, and inflammation-related pathways. In vivo experimental results demonstrated that LQAtta could alleviate liver injury, steatosis, and inflammation induced by NASH, thereby slowing down the disease process. Additionally, LQAtta inhibited the expression and phosphorylation of NF-κB protein, playing a role in preventing NASH.

In this study, the combination of mass spectrometry analysis, network pharmacology, and animal experiments preliminarily elucidated the potential of LQAtta to treat NASH through NF-κB pathways.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are recognized risk factors for dyslipidemia. Current prediction models that rely solely on dyslipidemia polygenic risk score (PRS) have certain limitations. We aimed to validate simple indexes for NAFLD and NASH as predictors of dyslipidemia using the PRS. This study utilized cohort data from an urban population-based dataset comprising 48,263 South Koreans. The incidence of dyslipidemia was higher in men than in women (32.4% and 27.8%; p < 0.001). The PRS model predicted dyslipidemia more accurately in men (AUROC [95% confidence intervals]: 0.645 [0.636-0.754]). Notably, integrating the fatty liver index (FLI) and fibrotic NASH index (FNI) with the PRS model resulted in the highest accuracy in diagnosing dyslipidemia, particularly in men (AUROC [95% confidence intervals]: 0.704 [0.698-0.711]). In conclusion, a predictive model combining the PRS with FLI and FNI was validated. This model offers more accurate predictive value for diagnosing dyslipidemia, particularly in East Asian men. Thus, our study has the clinical potential for identifying high-risk individuals and determining preventive measures for dyslipidemia in a sex-specific manner.

Due to rapid economic development and the unique lifestyles, cultures and customs of Hangzhou, non-alcoholic fatty liver disease (NAFLD) has attracted widespread attention, with a prevalence rate of 35-45%. In this study, we used the Chinese version of the Chronic Liver Disease Questionnaire for NAFLD (CLDQ-NAFLD) to investigate the current health-related quality of life (HRQL) among patients with NAFLD and analyse the influencing factors, which provides a reference for improving the patients' HRQL.

A cross-sectional design.

This study was conducted from March 2022 to March 2023 at a tertiary hospital in Hangzhou.

All patients with NAFLD included in this study were diagnosed using FibroScan, with a controlled attenuation parameter ≥248 dB/m.

The primary outcome of the study was the HRQL score, which was assessed using the Chinese version of the CLDQ-NAFLD.

A total of 502 patients with NAFLD were enrolled in this study (mean age 1.79±13.49 years; 69.7% male). The overall HRQL score was 5.89 (5.33, 6.36), and the fatigue dimension score was the lowest at 5.17 (4.33, 6.00). Multiple linear regression analyses revealed that poor HRQL score was correlated with other marital status (β=-0.096, p=0.036), liver stiffness ≥10.3 (kPa) (β=-0.110, p=0.017), regular exercise (β=-0.121, p=0.006), sex (β=-0.114, p=0.012) and alanine transaminase (ALT) levels (β=-0.139, p=0.002). A monthly income >10 000 (renminbi) was associated with a significantly higher HRQL score.

This cross-sectional survey conducted in Hangzhou, China, revealed that HRQL is impaired among patients with NAFLD. This study revealed a significant association between HRQL and sociodemographic factors, including sex, monthly income and marital status, alongside clinical factors such as liver stiffness, regular exercise and ALT level. Emphasising optimal care management is essential to improve HRQL in patients with NAFLD.

Quinoa is a food containing dietary fiber and various phytochemicals with high nutritional value, which has a structure similar to whole grains. This randomized controlled trial aimed to assess the effect of substituting grains with quinoa on cardiovascular risk factors and liver function in individuals with Non-alcoholic fatty liver disease (NAFLD).

Forty-six participants were randomly assigned to either a control group, which maintained their regular grain-based diet, or an intervention group, where grains were replaced with quinoa for 12 weeks. Participants in the quinoa group were instructed to substitute grains with quinoa during lunch for 12 weeks. The primary outcome was to assess the changes in the Controlled Attenuation Parameter (CAP) score between the intervention and control groups. Secondary outcomes included the difference in cardiometabolic risk factors and liver function between the two groups.

Following 12 weeks of intervention with quinoa, a significant reduction in weight, and waist circumferences (WC) were observed compared to the control group (p value < 0.05). Furthermore, even after adjustment for weight change, there was a significant reduction in CAP score, serum levels of low-density lipoprotein cholesterol (LDL-C), and an improvement in homeostatic model assessment for insulin resistance (HOMA-IR) in the quinoa group compared to the control group after the 12 weeks (p value < 0.05). However, no significant changes were observed in other measured parameters, including liver enzymes, fibroscan, fasting plasma glucose, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and inflammatory factors.

This study demonstrated that replacing grains with quinoa led to a significant improvement in the CAP score, HOMA-IR, and LDL-C in individuals with NAFLD, regardless of any weight changes. Thus, incorporating quinoa-a plentiful and low-cost source of bioactive compounds-into the diets of NAFLS patients as a staple food could improve several cardiometabolic risk factors in these individuals.

IRCT20100524004010N37.

Formononetin (FMN) is a common natural metabolite that can be extracted and isolated from some common botanical drugs. In recent years, FMN has garnered increasing attention due to its beneficial biological activities. In this paper, we systematically summarize the sources of FMN and provide a comprehensive review of its pharmacological activities and molecular mechanisms, co-administration, toxicity, derivatives, and drug delivery systems in the last 5 years. The study results found that FMN has a wide range of pharmacological activities in neurological disorders, organ damage and cancer, showing great potential for clinical application and broad prospects. Researchers are exploring various types of delivery systems, including nanoparticle carriers, ligand modifications and polymer microspheres. These advanced delivery systems can enhance the stability of FMN, prolong its release time in vivo, and improve targeting, thereby optimizing its therapeutic efficacy and reducing side effects, and greatly improving its bioavailability. In conclusion, FMN is a natural metabolite with considerable research value, and its diverse biological activities make it a promising candidate for drug development and medical research.

Ectopic fat deposition, involving lipid infiltration within organs and fat accumulating surrounding organs, plays a crucial role in the development of metabolic abnormalities in obesity. Current imaging measurements of obesity primarily focus on lipid infiltration within liver, neglecting fat deposition in other areas. This study aims to explore the methods of measuring and correlating different types of abdominal ectopic fat deposition in obese patients using magnetic resonance imaging (MRI) and ultrasound techniques, and to investigate the relationship between these fat parameters and obesity-related metabolic markers.

Abdominal ectopic fat deposition including liver fat content, mesenteric fat thickness (MFT), perirenal fat thickness (PrFT) and preperitoneal fat thickness (PFT) were measured in 220 overweight/obese patients using both MRI and ultrasound techniques. Correlation analysis validated the concordance of fat parameters at specific sites between the two imaging methods and identified the cutoff values of hepatic attenuation coefficient (AC) for diagnosis of liver steatosis. Additionally, we investigated the correlation between fat parameters by both methods and obesity-related metabolic markers.

Ultrasonic measurement of PrFT and hepatic AC both had high correlation with PrFT (r = 0.829, p < 0.001) and hepatic Proton-density fat fraction (PDFF, r = 0.822, p < 0.001) measured via MR. Hepatic AC cutoff values for diagnosing mild, moderate, and severe fatty liver were 0.705 dB/cm/MHz (AUC = 0.922), 0.755 dB/cm/MHz (AUC = 0.923), and 0.875 dB/cm/MHz (AUC = 0.890) respectively. Hepatic AC correlated significantly with AST and ALT (r = 0.477 ~ 0.533, p < 0.001). MFT measured by ultrasound were positively associated with glycated hemoglobin (r = 0.324 ~ 0.371, p < 0.001) and serum triglyceride levels (r = 0.303 ~ 0.353, p < 0.001). PrFT measured by both methods showed significant positive correlations with serum creatinine levels (r = 0.305 ~ 0.308, p < 0.001).

Both MRI and ultrasound demonstrate metabolic correlations in quantifying mesenteric, hepatic, and perirenal fat. In addition to assessment of liver fat content, the measurements of ectopic fat deposition by MRI or ultrasound are a simple and crucial way for comprehensive fat evaluation in individuals with overweight/obesity.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease that ranges from metabolic dysfunction-associated steatotic liver (MASL) to metabolic dysfunction-associated steatohepatitis (MASH), and may eventually progress to cirrhosis and hepatocellular carcinoma (HCC). The underlying mechanism of MASLD remains incompletely understood. This study aimed to identify key gene implicated in MASLD pathogenesis and validate its correlation with disease severity through an integration of bioinformatics and experimental approaches. Liver transcriptome data from MASLD patients were obtained from the Gene Expression Omnibus (GEO) database. A diet-induced MASLD mouse model was developed, and liver RNA-sequencing was performed. Liver specimens and clinical data from patients were collected for further analysis. A total of 120 differentially expressed genes (DEGs) were shared between datasets GSE89632 and GSE213621, with functional enrichment in inflammatory, metabolic, and cell cycle-related pathways. Protein-protein interaction (PPI) network analysis identified three modules associated with MASLD, with the cell cycle-related module being the most notable. EEF1A2 was identified as a novel hub gene and revealed to be elevated with MASLD progression through dataset analysis. EEF1A2 was confirmed to be highly expressed in the livers of both MASLD mouse models and patients. Moreover, the increased expression of EEF1A2 in MASH was positively correlated with higher serum alanine aminotransferase (ALT), alanine aminotransferase (AST), total cholesterol (TC), and body mass index (BMI). In conclusion, EEF1A2 is a novel hub gene significantly associated with MASLD severity and is a promising biomarker and therapeutic target for MASLD.

Metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of fatty liver disease, is characterized by liver inflammation and fibrosis, with an emerging interest in fibroblast growth factor (FGF)-21 analogs, particularly pegbelfermin (PGBF). This study evaluates the efficacy and safety of PGBF in treating MASH-associated hepatic fibrosis.

This meta-analysis followed Cochrane guidelines and PRISMA standards. A comprehensive search of databases up to January 2023 focused on randomized controlled trials (RCTs) comparing PGBF to placebo for MASH. Meta-analyses were performed with RevMan 5.4 using a random-effects model.

Data from 452 participants across three RCTs were analyzed. Significant improvements in adiponectin concentration were observed in both the 10 mg [MD = 18.23, 95% CI (6.35, 30.11), p = 0.003] and 20 mg [MD = 18.09, 95% CI (5.88, 30.31), p = 0.004] PGBF groups compared to placebo. Significant reductions in PRO-C3 concentration were noted in both the 10 mg [MD = -25.50, 95% CI (-43.95, -7.05), p = 0.007] and 20 mg [MD = -19.54, 95% CI (-33.33, -5.76), p = 0.005] groups. Significant improvement in MASH was seen in the 10 mg group [RR = 2.84, 95% CI (1.18, 6.78), p = 0.02] but not in the 20 mg group. No significant improvements in liver stiffness, Modified Ishak scores, collagen proportionate area, ALT and AST levels, or treatment-emergent adverse events (TEAEs) were observed in either dosage group.

Pegbelfermin, a promising therapy for MASH fibrosis, has demonstrated effectiveness at 10 mg, significantly improving MASH and biomarkers including adiponectin and PRO-C3, while maintaining a generally safe profile.

With a steadily rising prevalence, nonalcoholic fatty liver disease (NAFLD) was a leading global cause of liver-related health problems. In the clinical management of NAFLD, various western pharmaceuticals were widely utilized. This network meta-analysis aimed to evaluate the effectiveness of common western medications for NAFLD patients.

We systematically reviewed and screened articles based on predesigned criterion about western medications for NAFLD, which were from Embase, Cochrane Library, PubMed, CNKI, WanFang, and China Science and Technology Journal Database until August 1, 2024. Eligible studies included randomized controlled trials of patients aged 18 or older with NAFLD, comparing Western medicines to placebos or other Western medicine treatments. The risk of bias assessment tool 2.0 from the Cochrane system was used to assess the quality of the included articles. A Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 with a random-effects model and Markov Chain Monte Carlo methods. Treatment rankings were based on Surface Under the Cumulative Ranking Curve (SUCRA) values, and heterogeneity was assessed with I2 and Q statistics. The outcomes were analyzed in WinBUGS and visualized using Stata 14.0, generating network plots and cumulative probability rankings to compare treatment effects. The systematic review was registered in PROSPERO (CRD42024509176).

Based on 37 included articles involving 7673 patients, pioglitazone demonstrated the most significant effects in resolving nonalcoholic steatohepatitis without worsening fibrosis, increasing high-density lipoprotein cholesterol levels, and achieving a ≥ 2-point reduction in NAFLD activity scores (odds ratio [OR] = 0.09, 95% confidence interval [CI]: 0.01 to 0.81), with a SUCRA probability of 91.4%. Aldafermin showed remarkable effects in improving liver function markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transpeptidase, with cumulative probabilities of 90% for ALT and 69.8% for AST. Cluster analysis revealed that Resmetirom and Aldafermin were superior options for enhancing liver function, while pioglitazone emerged as the best treatment for the comprehensive improvement of NAFLD.

Pioglitazone outperformed other western medicines in terms of overall efficacy when treating NAFLD, but Aldafermin and Resmetirom showed superior improvement in liver function. This study provided a certain level of support for the use of specific clinical medications.