Fibroblast Growth Factor 21

Comparative Efficacy and Safety of Resmetirom and Efruxifermin for Metabolic Dysfunction-Associated Steatohepatitis: A Network Meta-Analysis of Randomized Controlled Trials.

Doha Jaber, Inas Jaber, Ayah Abu Lehia +2 more

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver condition and a major cause of cirrhosis, hepatocellular carcinoma, and liver transplantation. Resmetirom, a thyroid hormone receptor β agonist, and Efruxifermin, a fibroblast growth factor 21 analogue, have shown promise in improving hepatic fat fraction (HFF) and liver enzyme levels. This study systematically compares the efficacy and safety of Resmetirom and Efruxifermin in treating MASH.

Lycium barbarum polysaccharides as prebiotics prevent colorectal cancer liver metastasis in non-alcoholic fatty liver disease by modulating gut microbiota-FGF21-PI3K-AKT axis.

Shuai Zhao, Zhenyao Tan, Jiaxin Suo +1 more

Colorectal cancer liver metastasis (CRLM) is the leading cause of death in colorectal cancer, and nonalcoholic fatty liver disease (NAFLD) promotes CRLM. Lycium barbarum polysaccharides (LBPs), bioactive metabolites of the traditional medicinal plant Lycium barbarum L, inhibit the progression of colorectal cancer and NAFLD by regulating gut microbiota composition. However, their roles in preventing CRLM under NAFLD conditions remain unclear. This study aimed to investigate the preventive effect of LBPs on liver metastasis of colorectal cancer in the context of NAFLD and explore its potential mechanisms.

Efficacy and safety of fibroblast growth factor 21 analogs in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis: A systematic review and network meta-analysis.

Marwa Muhammed Abdeljawad, Mohammed Tarek Hasan, Areeba Fareed +7 more

Metabolic dysfunction-associated steatotic liver disease has emerged as a global public health concern. Fibroblast growth factor 21, a liver hormone, is gaining interest because of its ability to regulate metabolism and improve metabolic dysfunction-associated steatotic liver disease. In this network meta-analysis, we investigated the efficacy of these treatments in treating metabolic dysfunction-associated steatotic liver disease. A comprehensive search was conducted across electronic databases, including PubMed, Scopus, the Cochrane Library, and Web of Science, till August 2025. We used R software to analyze data using a random effects model. Heatmaps were used to visualize the included interventions' ranking. We included 9 clinical trials comprising 1277 patients. Among them, 284 received efruxifermin, 263 received pegbelfermin, 151 received pegozafermin, 65 received efimosfermin, 139 received MK-3655, and 375 received a placebo. Pegozafermin and efruxifermin were effective in improving liver fibrosis (RR, 3.89-3.93, P < .05; RR, 2.23-1.91, P < .05, respectively), whereas the other interventions did not yield statistical significance. Efimosfermin α, efruxifermin, and pegozafermin improved different metabolic parameters, including adiponectin, hemoglobin A1c, and non-high-density lipoprotein. However, no significant differences were observed in body weight and low-density lipoprotein. For liver enzymes, efimosfermin α had the greatest reduction of alanine aminotransferase and aspartate aminotransferase, whereas efruxifermin was most effective in reducing γ-glutamyl transferase levels. The odds of adverse events were higher in pegozafermin, efimosfermin, and efruxifermin groups, mainly attributed to mild to moderate gastrointestinal adverse events. In conclusion, efruxifermin and pegozafermin are promising therapeutic options with a tolerable adverse event profile; meanwhile, efimosfermin α showed promising results in improving metabolic parameters, with histologic results yet to be published. SIGNIFICANCE STATEMENT: This meta-analysis evaluates the efficacy of fibroblast growth factor 21 analogs in improving metabolic dysfunction-associated steatotic liver disease. Efruxifermin and pegozafermin were the most significant in improving liver fibrosis; moreover; significant improvements in some metabolic parameters were observed with efimosfermin α, efruxifermin, and pegozafermin.

Metabolic-Associated Steatotic Liver Disease and FGF21 Dysregulation in Seipin-Deficient and BSCL2-Associated Celia's Encephalopathy Murine Models.

Silvia Cobelo-Gómez, Lía García-Formoso, Antía Fernández-Pombo +7 more

Seipin, a protein encoded by the BSCL2 gene, plays a crucial role in lipid metabolism, and some pathogenic biallelic variants cause lipodystrophy and associated metabolic disorders. This study investigates liver pathology and dysregulation of the FGF21 signalling pathway in two mouse models: Bscl2-/- (knock-out) and Bscl2Celia/Celia (knock-in). We evaluated liver histopathology using H&E and Oil red O staining, assessed hepatic triglyceride levels via enzymatic assays, and analyzed gene expression of key FGF21-related components (Fgf21, Ppargc1a, Fgfr1, and Klb) using quantitative real-time PCR. The liver histology was scored using the NAFLD activity score (NAS) system. Both models exhibited hepatic steatosis and inflammatory features. The Bscl2-/- mice showed more pronounced liver damage, including ballooning degeneration and fibrosis. Gene expression analysis revealed a significant increase in Fgf21 in both models, suggesting an adaptive response to liver injury. Notably, Fgfr1 and Ppargc1a expression was moderately elevated in severe neurologically affected mice showing less hepatic involvement, suggesting a potential adaptive or protective association of these genes with reduced steatosis. Seipin deficiency leads to metabolic-associated steatotic liver disease and dysregulated FGF21 signalling. These findings provide insight into the pathophysiological mechanisms of lipodystrophy and liver disease and suggest that the FGF21 pathway could be a therapeutic target for treating seipin-related metabolic disorders.

Organokine-Mediated Crosstalk: A Systems Biology Perspective on the Pathogenesis of MASLD-A Narrative Review.

Sandra Maria Barbalho, Lucas Fornari Laurindo, Vitor Engracia Valenti +3 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic condition with a complex pathophysiology involving multiple organs. Organokines, including hepatokines, myokines, cardiokines, renokines, osteokines, and adipokines, play central roles in lipid metabolism, glucose homeostasis, inflammation, and fibrosis. Dysregulation of these signaling molecules contributes to the progression of MASLD and its systemic complications. This review examines the role of organokine-mediated crosstalk between the liver and peripheral organs (e.g., muscle, heart, kidneys, bone, and adipose tissue) in the pathogenesis of MASLD. Key molecules, such as myostatin, FGF-21, IL-6, and adiponectin, influence insulin sensitivity, lipid metabolism, and inflammation. Some organokines have protective effects (e.g., FGF-21, irisin, and klotho), while others, such as myostatin and fetuin-A, exacerbate insulin resistance and fibrosis. These findings suggest that targeting organokines could provide potential biomarkers and therapeutic strategies for MASLD. Future research should focus on elucidating the molecular mechanisms and assessing the role of organokines in the prevention and treatment of MASLD.

Chinese medicine formulation Mailuoning attenuates high-fat diet-induced obesity by regulating thermogenesis through activating the peroxisome proliferator-activated receptor α/fibroblast growth factor 21 axis.

Wangya Jia, Sijia Wu, Keke Wang +4 more

Mailuoning is a Chinese medicine formulation known for its efficacy in clearing heat, nourishing yin, activating blood circulation, and resolving blood stasis. In traditional Chinese medicine, Mailuoning is considered to have potential benefits in improving obesity. Our previous research has demonstrated that Mailuoning could effectively alleviate non-alcoholic fatty liver disease (NAFLD), a metabolic disorder with pathophysiological similarities to obesity. However, the alleviating effects of Mailuoning on obesity have yet to be fully elucidated, and further investigation is required to confirm its therapeutic effect.

The combination of zalfermin and semaglutide has additive therapeutic effects in a diet-induced obese and biopsy-confirmed mouse model of MASH.

Jenny Norlin, Maria Dermit, Nikos Sidiropoulos +7 more

Fibroblast growth factor 21 (FGF21) analogs have significant therapeutic potential in metabolic dysfunction-associated steatohepatitis (MASH) but limited body weight effects in patients with MASH. This study investigated the effect of combined treatment with the FGF21 analog zalfermin and the glucagon-like peptide-1 receptor agonist semaglutide on body weight and plasma and liver biochemistry and histology in a mouse model of MASH. Amylin liver nonalcoholic steatohepatitis diet-induced obese-MASH mice with biopsy-confirmed MASH and fibrosis were administered (subcutaneous [SC], daily [QD]) vehicle, zalfermin (0.05 or 0.2 mg/kg), semaglutide (3 or 120 µg/kg), or zalfermin 0.05 mg/kg + semaglutide 3 µg/kg for 8 weeks (n = 11-12 per group). Vehicle-dosed (SC, QD) chow-fed mice served as normal controls (n = 10). Pre- to post-liver biopsy histology was compared for within-subject evaluation of changes in non-alcoholic fatty liver disease Activity Score (NAS), fibrosis stage, and quantitative histology. Additional endpoints included plasma/liver biochemistry and liver RNA sequencing. Combined low-dose zalfermin and semaglutide treatment resulted in super-additive body weight loss (-18%) vs. individual low-dose monotherapies (zalfermin, -6%; semaglutide, -4%) and was equally effective as high-dose zalfermin monotherapy (-16%) and semaglutide (-15%). Low-dose combination therapy promoted greater benefits on transaminases, total cholesterol and triglycerides, NAS, steatosis, and inflammation vs. individual low-dose monotherapies and high-dose semaglutide, and high-dose zalfermin was as effective as the low-dose combination therapy on most endpoints. Combination treatment reduced gene expression markers of fibrosis to a greater degree than monotherapies. In conclusion, combined low-dose zalfermin and semaglutide, as well as high-dose zalfermin, resulted in beneficial effects on body weight and biochemical and histological endpoints, supporting the clinical development of zalfermin as therapy for patients with MASH.

Prospects of late-stage development agents in the treatment of metabolic dysfunction-associated steatohepatitis.

Brian Lee, Ussama Ghumman, Lisa D Pedicone +2 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a spectrum of pathology involving fatty liver disease that may progress to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. The prevalence of MASLD and metabolic dysfunction-associated steatohepatitis (MASH) continues to increase, mirroring the rise in global prevalence of related comorbidities such as obesity and type 2 diabetes mellitus. Due to the alarming rise of these comorbidities, a greater proportion of the population is at risk for developing MASLD and MASH. As such, there has been a significant effort to develop effective therapies for MASLD and MASH. Recently, the U.S. Food and Drug Administration approved resmetirom, a selective thyroid hormone receptor-beta agonist, as the first treatment for patients with MASH. In India, the Drug Controller General of India approved saroglitazar, a dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist, for the treatment of MASLD. Currently, we have various drug classes, including liver-specific therapies, in Phase 3 development with even more agents earlier in the pipeline. This review will discuss prospective therapies in later stages of development such as thyroid hormone receptor-beta agonists, PPAR agonists, glucagon-like peptide-1 receptor agonists, fibroblast growth factor 21 agonists, and fatty acid synthase inhibitors.

A Novel GLP-1 and FGF21 Fusion Protein for the Treatment of Non-alcoholic Steatohepatitis (NASH).

Zhipeng Zhang, Yanqin Ma, Cheng Xie +5 more

The objective of this study was to develop and produce a novel fusion protein that combines GLP-1 (glucagon-like peptide-1) and FGF21 (fibroblast growth factor 21), with the aim of achieving synergistic pharmacological effects through the targeting of dual pathways, followed by validation of these effects in a non-alcoholic steatohepatitis (NASH) model.

Steatotic liver disease and cancer: from pathogenesis to therapeutic targets.

Zhihong Yang, Zhenjie Liu, Wanqing Liu +1 more

As environmental exposomes are changing with time, so are liver diseases around the globe. Due to an increasing prevalence of overnutrition and sedentary lifestyle in the global population, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis have been increasing steadily in the past decades. Alcohol consumption is another common risk factor for liver diseases such as alcohol-associated liver disease or hepatitis. For both alcohol-associated and metabolic dysfunction-associated liver diseases, hepatocyte injuries are among the early events during the development of steatotic liver disease (SLD). Hepatic inflammation and fibrosis ensue with recurring hepatic damages owing to immune responses from multiple immune cell types, particularly neutrophils, Kupffer cells and monocyte-derived macrophages in response to damage-associated and pathogen-associated molecular patterns, and extracellular matrix production predominantly from hepatic stellate cells. Both environmental and genetic factors contribute to the SLD pathogenesis. Common environmental risk factors include obesity, type 2 diabetes mellitus, unhealthy diets, sedentary lifestyle and excessive alcohol consumption. Numerous genome-wide association studies have identified multiple genetic variants associated with key traits of SLD, including patatin-like phospholipase domain containing 3 rs738409, transmembrane 6 superfamily member 2 rs58542926, membrane bound O-acyltransferase domain containing 7 rs641738 and hydroxysteroid 17 beta-dehydrogenase 13 rs72613567. Cirrhosis and liver cancer are common late-stage developments of various chronic liver diseases; however, there are pathological differences according to disease aetiologies. Therefore, preventive and therapeutic intervention strategies should align with the underlying causal and modifiable factors. Currently, multiple therapeutics have been developed or approved for treatment of SLD, including thyroid hormone receptor β agonists, glucagon-like peptide 1 receptor agonists and fibroblast growth factor 21 analogues. The concept of this review was motivated and inspired by the Seventh Annual Symposium of Chinese American Liver Society held in San Diego, California, USA on 13-14 November 2024.

TSG attenuated NAFLD and facilitated weight loss in HFD-fed mice via activating the RUNX1/FGF21 signaling axis.

Zhen-Lin Huang, Shao-Bo Zhang, Shang-Fu Xu +5 more

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by steatosis in hepatocytes and is now becoming the major cause of liver-related mortality. Fibroblast growth factor 21 (FGF21) is an endocrine hormone mainly secreted by the liver, which can bind to its receptor (FGFR) and co-receptor beta klotho (KLB) to form a receptor complex, exerting its lipid-lowering function. 2,3,5,4'-Tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG), a natural compound isolated from Polygonum multiflorum Thunb, has shown excellent activity in lowering lipid content and efficacy in improving NAFLD. In this study we investigated whether FGF21 was implicated in the therapeutic effect of TSG in NAFLD mice. NAFLD was induced in mice by feeding with a high-fat diet (HFD) for 12 weeks, and treated with TSG (20, 40 mg·kg-1·d-1, i.g.) during the last 4 weeks. We showed that TSG treatment significantly alleviated NAFLD in HFD-fed mice evidenced by reduced hepatic triglyceride (TG) and non-esterified fatty acids (NEFA), diminished lipid droplets and decreased NAFLD activity score (NAS) in liver tissues. We demonstrated that TSG treatment significantly increased the mRNA and protein levels of FGF21 in vitro and in vivo, and reduced lipid accumulation in both the liver and adipose tissues. Transcriptomics analysis revealed that TSG treatment significantly increased the nuclear translocation of a transcription factor RUNX1. Knockdown of Runx1 in HFD-fed mice eliminated the efficacy of TSG in alleviating NAFLD, reducing hepatic lipid accumulation and regulating FGF21 signaling pathway in liver and adipose tissues. In conclusion, TSG alleviates NAFLD by enhancing the FGF21-mediated lipid metabolism in a RUNX1-dependent manner.

FGF21 deletion mildly exacerbates hepatic dysfunction in GAN diet and alcohol fed rats.

Peter Aldiss, Malte Hasle Nielsen, Hayley Burm +4 more

Fibroblast growth factor 21 (FGF21) analogues are in clinical development as treatments for metabolic and alcohol-associated liver disease. The aim of this study was to characterize the first FGF21 knockout (KO) rat line to validate its utility as a translational animal model that recapitulates human disease. We generated an FGF21 KO rat model and exposed 6-month-old WT and KO rats to either chow (n = 8 per genotype) or the obesogenic GAN (Gubra Amylin NASH) diet (n = 16 per genotype) for 12 weeks. Lack of endogenous FGF21 increased plasma transaminases, liver weight, and total levels of liver TG in GAN-fed FGF21 KO rats. FGF21 KO had no impact on body weight, glycaemic traits, or MASH histological endpoints, including hepatic steatosis, NAS score, lobular inflammation, ballooning degeneration, fibrosis stage, or the liver transcriptome. Finally, we demonstrate that endogenous FGF21 does not regulate drinking behaviour in rats.

B1344 ameliorates non-alcoholic steatohepatitis in HFCD-HF/G-induced mice: exploring the therapeutic efficacy and mechanism of a novel FGF21 analogue.

Zhiwei Chen, Tao Liu, Ping Huang +6 more

The endocrine cytokine, fibroblast growth factor 21 (FGF21), shows therapeutic potential for non-alcoholic steatohepatitis (NASH) but has pharmacokinetic limitations. B1344 is a modified PEGylated FGF21 analogue with enhanced stability and bioactivity. Researches are required to further explore its effect and possible mechanisms against NASH. C57BL/6J mice were induced by 10-week high-fat/calorie diet with high fructose/glucose water (HFCD-HF/G). B1344 was then administered for 8 weeks. Systemic metabolic parameters, hepatic injury, insulin resistance, adipose tissue (AT) function, and FGF21 resistance were evaluated. RNA-sequencing of liver and adipose tissues was carried out. B1344 attenuated HFCD-HF/G-induced metabolic disorder and hepatic damages. Liver transcriptomics revealed its multi-target modulation of lipid metabolism, inflammation, fibrosis, etc. Systemic insulin resistance and downsream signaling in liver, muscle and AT was improved by B1344. Notably, it restored AT dysfunction and alleviated FGF21 resistance. AT RNA-sequencing further identified its regulation in inflammation, angiogenesis, hypoxia and senescence. Collectively, B1344 demonstrates robust efficacy against NASH in HFCD-HF/G-induced mice. The multi-target modulation in liver and AT including FGF21 resistance was involved in its underlying mechanisms. This study not only provides support for further clinical trials of B1344, but also benefits deeper understanding of FGF21 function.

Safety and efficacy of once-weekly efruxifermin versus placebo in metabolic dysfunction-associated steatohepatitis (HARMONY): 96-week results from a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial.

Mazen Noureddin, Juan P Frias, Guy W Neff +15 more

Efruxifermin is a bivalent fibroblast growth factor 21 analogue in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). This trial aimed to prospectively assess the safety and efficacy of efruxifermin administration for 96 weeks in individuals with MASH and moderate (stage 2; F2) or severe (stage 3; F3) fibrosis.

Combined Cold Exposure and Exercise Improves NAFLD: Mechanistic Insights.

Xue Geng, Zhijian Rao, Jianhong Zhang +7 more

Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the global population and poses a remarkably serious threat to human health.

Protein phosphatase 6 regulates metabolic dysfunction-associated steatohepatitis via the mTORC1 pathway.

Zhengshuai Liu, Shuang Wei, Yang Jiang +15 more

Metabolic dysfunction-associated steatohepatitis (MASH) is a serious chronic liver disease for which therapeutic options are limited. Although fibroblast growth factor 21 (FGF21) analogs have shown therapeutic promise for MASH in multiple preclinical and clinical studies, their underlying mechanisms of action remain elusive.

New Names, New Drugs, Better Outcomes in Steatotic Liver Disease.

Matthew Peverelle, Mzamo Mbelle, Deepak Joshi

Steatotic liver disease (SLD) is a growing cause of chronic liver disease, with potential progression to cirrhosis, hepatocellular carcinoma (HCC), and liver failure. Previously known as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), new terminology, including metabolic-dysfunction associated steatotic liver disease (MASLD) and metabolic-dysfunction associated steatohepatitis (MASH), was introduced to improve diagnostic clarity and reduce stigmatization. MASLD is now recognized as the hepatic manifestation of the metabolic syndrome and is the most common cause of liver disease in the UK, affecting up to 20% of adults. The incidence of MASLD-related cirrhosis and HCC is expected to rise significantly by 2030, highlighting the need for early diagnosis and treatment. For over two decades, effective medical therapies for MASLD were elusive. However, recent trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), thyroid hormone receptor-β (THR-β) agonist resmetirom, and fibroblast growth factor 21 (FGF21) agonists have shown promising results in reversing steatohepatitis and potentially fibrosis. These agents potentially offer new disease-modifying treatment options for MASLD, with GLP-1 RAs particularly effective in achieving weight loss and all drugs showing promising histological benefits in patients with MASH. This review summarizes nomenclature changes, provides an update on the UK's SLD burden, with a particular focus on MASLD and MASH, and discusses new therapeutic strategies for managing this complex and increasingly prevalent condition.

New Approach Combination-Dosed Therapy for Nonalcoholic Steatohepatitis Versus Vitamin E: A Randomized Controlled Trial.

Amr Y Zakaria, Rehab Badawi, Hasnaa Osama +2 more

There is currently no US Food and Drug Administration-approved remedy for nonalcoholic steatohepatitis (NASH). The present study evaluated the efficacy of N-acetyl cysteine (NAC) and rosuvastatin (RSV) compared with conventional vitamin E in patients with NASH.

Efruxifermin in Compensated Liver Cirrhosis Caused by MASH.

Mazen Noureddin, Mary E Rinella, Naga P Chalasani +16 more

In phase 2 trials involving patients with stage 2 or 3 fibrosis caused by metabolic dysfunction-associated steatohepatitis (MASH), efruxifermin, a bivalent fibroblast growth factor 21 (FGF21) analogue, reduced fibrosis and resolved MASH. Data are needed on the efficacy and safety of efruxifermin in patients with compensated cirrhosis (stage 4 fibrosis) caused by MASH.

Evaluating Hepatokines in the Progression of Non-alcoholic Fatty Acid Liver Disease by Decoding Liver-Derived Molecular Pathologies.

Shehwar Ahmed, Muhammad Ahmed, Faizan Abbas +6 more

Non-alcoholic fatty liver disorder (NAFLD), also called metabolic dysfunction-associated steatotic liver disease (MASLD), is a leading cause of global liver disorders. Hepatokines are increasingly being used in the diagnosis of NAFLD. This study evaluated the association between the hepatokines and NAFLD progression and guided further therapeutic research. Data search was conducted across PubMed, Embase, Scopus, and Web of Science up to March 2025. Studies that assessed hepatokines in NAFLD were selected based on defined inclusion criteria. The Newcastle-Ottawa Scale (Version 2011), the Cochrane Risk of Bias 2 (RoB 2) tool, and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology were used to evaluate the RoB and the certainty of evidence. Pooled estimates were synthesized by using a random-effects meta-analysis model. Ten studies passed the eligibility criteria and involved a pooled sample size of 4,215 participants. Meta-analysis of six studies revealed that an increase in hepatokine levels was modestly correlated with NAFLD (odds ratio (OR) 1.11; 95% confidence interval (CI) 1.01-1.22; P = 0.037; I² = 84%). Individual biomarkers such as Fetuin-A, angiopoietin-like protein 8 (ANGPTL8), fibroblast growth factor 21 (FGF21), and retinol-binding protein 4 (RBP4) showed varying degrees of correlation. RoB was moderate across eight studies, low and high across one study each, and GRADE assessments displayed low to moderate quality of evidence. The research findings established a steady connection between NAFLD and variation in hepatokine levels. Fetuin-A and FGF21 showed promise as biomarkers against NAFLD diagnosis. However, uncertainty remained because of high variability and moderate levels of experimental bias. Further research needs to be conducted through standardized methods for assays in multicenter longitudinal studies to confirm hepatokine diagnostic and therapeutic effectiveness in treating patients with NAFLD.

FAM172A deletion aggravates high fat diet-induced MASLD via the eIF2α-ATF4-FGF21 loop.

Herui Wei, Meixin Gao, Shiwei Wang +5 more

Inhibition of endoplasmic reticulum stress (ERS) can effectively improve the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we attempted to further explore the mechanism of Fam172a in high fat diet (HFD) induced-MASLD.

Acalabrutinib alleviates metabolic dysfunction-associated steatotic liver disease by regulating bile acid metabolism.

Yanbo Wang, Shiwei Chen, Bingjue Ye +5 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic of chronic liver disease currently lacking effective treatment. Evaluating the therapeutic effects of existing drugs on MASLD is a time and cost-effective strategy. Bruton's tyrosine kinase (BTK) is an inflammatory signaling molecule playing an important role in the progression of MASLD. Aclabrutinib, a BTK inhibitor approved for treating mantle-cell lymphoma and chronic lymphocytic leukemia, has not been investigated for its potential to treat MASLD. This study examined the therapeutic effects and mechanisms of aclabrutinib on MASLD using a high-fat diet-induced mouse model. Results demonstrated significant alleviation of pathological parameters associated with MASLD upon administration of aclabrutinib. TSE PhenoMaster results revealed that aclabrutinib increased energy expenditure in mice. Furthermore, aclabrutinib upregulated the expression of genes associated with thermogenesis and lipolysis in adipose tissues. Additionally, it inhibited the transcription of genes related to lipid absorption in the small intestine and liver, while increasing the expression of hormone-sensitive lipase, hepatic nuclear factor 4 alpha and fibroblast growth factor 21 in the liver. Further analysis indicated that aclabrutinib promoted the alternative pathway of bile acid synthesis while restoring gut microbiota homeostasis. The altered bile acid profiles upregulated G protein-coupled bile acid receptor 1 expression in adipose tissues as well as vitamin D receptor expression in liver and small intestine. Our findings suggest that by regulating bile acid metabolism and gut microbiota, aclabrutinib may promote thermogenesis and lipolysis, thereby alleviating MASLD. This study provides novel insights into clinical applications targeting BTK for treating MASLD.

Circulating Fibroblast Growth Factor-21 in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Ioanna Filimidou, Myrsini Orfanidou, Antonis Goulas +2 more

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is multifactorial. Fibroblast growth factor-21 (FGF-21) has been proposed to be associated with NAFLD, but data on its circulating levels in patients with NAFLD are to date conflicting.

Therapeutic Potential of Sotagliflozin in Animal Models of Non-alcoholic Fatty Liver Disease with and without Diabetes.

Nitin J Deshmukh, M S Kalshetti, Mohan Patil +2 more

Sotagliflozin, a dual SGLT1/2 inhibitor, enhances glucagon like peptide-1 (GLP-1) levels and GLP-1 receptor agonists are used to manage non-alcoholic fatty liver disease (NAFLD). Study investigates the effects of sotagliflozin on NAFLD, alone and combined with linagliptin, comparing outcomes in normoglycemic and hyperglycemic animal models.Obese fatty liver disease (FLD) model was induced by high-fat diet (HFD) feeding, while a diabetic non-alcoholic steatohepatitis (NASH) model was developed by administering a single dose of streptozotocin to neonatal mice, followed by HFD feeding post-weaning. At termination of the study, parameters including biochemical markers, inflammatory cytokines, hepatic lipid content, and histopathology were assessed.In NASH mice, sotagliflozin and linagliptin reduced hepatic triglycerides by 60% and 44%, respectively, and cholesterol by 46% and 49%. Their combination further decreased triglycerides by 68.5% and cholesterol by 83.9%. In FLD mice, sotagliflozin and linagliptin reduced triglycerides by 33% and 17%, respectively, and cholesterol by 46% and 21%. Combination treatment offered no benefit, reducing triglycerides by 38% and cholesterol by 27%. Both the treatments improved plasma fibroblast growth factor 21, hepatic interlukin-6, glucose tolerance, steatosis and mitigated fat pad weight, but their combination did not show additional benefit. However, combination treatment demonstrated added benefit in modulating NAFLD activity score, liver enzymes, glycogenated hepatic nuclei, plasma glucose and active GLP-1 levels.Study underscores sotagliflozin's potential to mitigate NAFLD and highlights the benefit of combining it with linagliptin in hyperglycemic NASH model, which showed limited efficacy in normoglycemic FLD mice.

[Study of the role of biomarkers in determining the course of non-alcoholic fatty liver disease in children with obesity].

A M Lebedeva, E V Pavlovskaya, M E Bagaeva +5 more

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world, especially among children. Studying the role of biomarkers in determining the course of NAFLD in obese children will make it possible to identify the disease at an early stage, assess the risks of progression and select individual approaches to therapy. The purpose of the research was to study the diagnostic role of noninvasive biomarkers in determining the severity of liver steatosis and fibrosis in obese children. Material and methods. 78 children from 11 to 17 years of age with exogenous constitutional obesity were examined. The children were divided into two groups: group 1 (n=59) - children with obesity and non-alcoholic fatty liver disease (NAFLD), group 2 (n=19) - children without NAFLD; in group 1, subgroups of children with simple liver steatosis (n=45) and non-alcoholic steatohepatitis (NASH) were identified (n=14). The study of lipid metabolism (total cholesterol, HDL, LDL, triglycerides), carbohydrate metabolism (glucose, insulin, HOMA-IR), blood serum level of fibroblast growth factor-21 (FGF-21), cytokeratin-18 (СK18), apoptosis factor associated with the FAS ligand (FASL), and visfatin has been conducted. All patients underwent ultrasound examination of the abdominal organs and liver elastography to determine the degree of liver fibrosis on the METAVIR scale and the degree of steatosis using a controlled attenuation parameter (CAP). Results. The level of the biomarkers CK-18 and FASL were significantly higher in children from Group 1 compared to those without NAFLD (1.26 [0.44; 1.57] vs 0.47 [0.43; 0.59] ng/mL, p=0.008 and 36.33 [25.57; 45.94] vs 22.55 [20.27; 26.41] pg/mL, respectively). Moreover, these levels increased with the degree of obesity. In patients with NASH, FASL levels showed a positive correlation with the degree of obesity (r=0.40), CK-18 with the stage of liver fibrosis (r=0.50), and visfatin with transaminase activity (r=0.65), fibrosis (r =1.0), and hepatic steatosis degree (r=0.60). FGF-21 demonstrated only weak correlations with the other studied biomarkers. The HIS and APRI indices were significantly higher in patients with NASH (46.46 [40.75; 53] vs 42.11 [36.88; 47.09], p=0.0006 and 0.25 [0.18; 0.36] vs 0.18 [0.15; 0.21], p=0.04 in patients with hepatic steatosis; and vs 40.02 [36.4; 44.85] and 0.16 [0.12; 0.22] in patients from Group 2, respectively). All patients had PNFI>9, indicating the presence of significant fibrotic changes. Correlation analysis showed that HIS and APRI indices were strongly associated with the degree of steatosis, alanine aminotransferase activity, and right liver lobe size. Conclusion. The use of biomarkers makes it possible to complement ultrasound diagnostics of NAFLD, providing more complete information about the severity of the disease without invasive procedures. The development and application of noninvasive methods for the diagnosis and prediction of NAFLD will in some cases avoid liver biopsy.

Association of FGF21 with Metabolic and Cardiovascular Diseases: A Mendelian Randomization Analysis.

Qingwen He, Yuguang Li, Renqiang Yu +1 more

Studies have covered a possible relevance between fibroblast growth factor 21 (FGF21) and obesity-related metabolic complications and cardiovascular disease (CVD). Nevertheless, whether FGF21 is a causative factor in these diseases is not known. Using a bidirectional, two-sample Mendelian randomization (MR) approach, this study sought to establish a causal relationship between FGF21 and seven metabolic diseases and six CVDs. A large-scale meta-analysis dataset of genome-wide association studies (GWAS) was analyzed to generate summary-level statistics for FGF21. The diseases we studied included non-alcoholic fatty liver disease (NAFLD), obesity, type 2 diabetes (T2DM), hypertension, gestational diabetes (GDM), gestational hypertension (GHTN), pre-eclampsia or eclampsia (PE), atherosclerosis, cardiomyopathy (CMP), coronary heart disease (CHD), coronary atherosclerosis, heart failure (HF), myocardial infarction (MI) and the corresponding summary GAWS data were retrieved from the FinnGen Biobank and IEU Open GWAS Project database. The inverse variance-weighted (IVW) algorithm was the primary approach utilized for the MR analysis. The MR-Egger regression and MR-PRESSO tests were implemented to evaluate horizontal pleiotropy. The heterogeneity of instrumental variables was subsequently assessed utilizing Cochran's Q statistics.When diseases are used as exposures, MR analysis results of the IVW method indicated that NAFLD (Beta=- 0.047, 95% CI=- 0.08 to - 0.014; p=0.006), obesity (Beta=0.087, 95% CI=0.021-0.153; p=0.009), T2DM (Beta=0.071, 95% CI=0.037-0.106; p<0.001) correlated causally with FGF21. Nevertheless, FGF21 was not causally related to the remaining metabolic diseases and CVDs, according to the results of the MR analysis (p>0.05). It was demonstrated that the aforementioned results were robust and devoid of pleiotropy.Our study supports a causal association between NAFLD, obesity, and T2DM with FGF21. No substantial evidence exists to establish a causal relationship between FGF21 and other diseases. This study provides opportunities for the early prevention and innovative therapy of NAFLD, obesity, and T2DM.

Pharmacological treatment for metabolic dysfunction-associated steatotic liver disease and related disorders: Current and emerging therapeutic options.

Xiang Zhang, Harry Cheuk-Hay Lau, Jun Yu

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.

Assessment of skeletal muscle alterations and circulating myokines in metabolic dysfunction-associated steatotic liver disease: A cross-sectional study.

Yolanda Real Martinez, Carlos Ernesto Fernandez-Garcia, Esther Fuertes-Yebra +11 more

Skeletal muscle alterations (SMAs) are being increasingly recognized in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and appear to be associated with deleterious outcomes in these patients. However, their actual prevalence and pathophysiology remain to be elucidated.

Evaluating the Effectiveness of Pegbelfermin in MASH-Associated Hepatic Fibrosis A Meta-Analysis and Systematic Review of Randomized Controlled Trials.

Muhammad Shahzil, Fariha Hasan, Syeda Kanza Kazmi +8 more

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.

Current priorities in research on metabolic-associated fatty liver disease based on the results of EASL - 2024.

Leonid L Pinsky, Mykola V Khaitovych, Olga A Golubovska +1 more

Aim: To systematize and comprehensively analyze scientific sources and studies on metabolic-associated steatotic liver disease (MASLD) based on materials from the European Congress of the European Association for the Study of the Liver (EASL - 2024)..