This review maps the metabolic dysfunction–associated steatohepatitis (MASH) drug landscape by mechanism and trial phase and how regulatory endpoints shape it. Phase 3 programs in non-cirrhotic MASH (F2–F3) still hinge on biopsy surrogates—MASH resolution without fibrosis worsening or ≥1-stage fibrosis improvement—while parallel cirrhosis trials target clinical outcomes (ascites, encephalopathy, variceal bleeding). Phase 2 increasingly uses noninvasive tests (MRI-PDFF, ALT, ELF/Pro-C3, VCTE/MRE) to show signal before histology. Late-stage leaders include resmetirom (THR-β; higher MASH resolution and fibrosis improvement vs placebo with mostly mild GI AEs), lanifibranor (pan-PPAR; phase 2 met both endpoints; phase 3 ongoing), and semaglutide (GLP-1 RA; phase 2 achieved MASH resolution without clear fibrosis benefit; phase 3 underway).

Earlier-phase pipelines span THR-β (VK2809, TERN-501), PPAR (PXL065, saroglitazar), incretin dual/triple agonists (pemvidutide, efinopegdutide, cotadutide, survodutide, tirzepatide, retatrutide), FXR (tropifexor, vonafexor), FGF19/FGF21 analogs (efruxifermin, pegozafermin; mixed data for aldafermin), de novo lipogenesis targets (ACC ± DGAT2; FASN inhibitor denifanstat), mitochondrial modifiers (HU6; MPC inhibitor MSDC-0602K negative on histology), genetic approaches (HSD17B13 siRNA/ASO; PNPLA3), and antifibrotics (belapectin). Combination therapy is a major theme (e.g., GLP-1 + FXR or ACC; THR-β + FXR), balancing added efficacy with AEs and adherence. Key roadblocks include biopsy variability (especially ballooning), placebo response, safety flags (e.g., OCA), and underrepresentation of high-risk groups. Momentum is strong toward induction-plus-maintenance regimens and greater reliance on validated noninvasive tests linked to hard outcomes.

Reference: Noureddin M. MASH clinical trials and drugs pipeline: An impending tsunami. Hepatology. 2025 Nov 1;82(5):1325-1340. doi: 10.1097/HEP.0000000000000860. Epub 2024 Mar 19. PMID: 38502810.

In this systematic review and network meta-analysis, two investigators conducted an updated network meta-analysis of 29 randomized trials (n=9,324; 2020–2024) in biopsy-proven metabolic dysfunction–associated steatohepatitis (MASH) to compare pharmacologic options. Searches of PubMed and Embase (Jan 1, 2020–Dec 1, 2024) identified studies spanning FGF21 analogs, FXR/ACC modulators, GLP-1/dual incretins, THR-β agonists, PPARs, and combo regimens. Co-primary endpoints were ≥1-stage fibrosis improvement without MASH worsening and MASH resolution without fibrosis worsening, analyzed via pairwise and network models. Interventions were ranked with surface under the cumulative ranking curve (SUCRA) to estimate each drug’s probability of being best-in-class and to produce a relative efficacy hierarchy.

Compared with placebo, several agents improved fibrosis without worsening MASH: pegozafermin, cilofexor+firsocostat, denifanstat, survodutide, obeticholic acid, tirzepatide, resmetirom, and semaglutide. Top SUCRA ranks were pegozafermin (79.92), cilofexor+firsocostat (71.38), and cilofexor+selonsertib (69.11). For MASH resolution without worsening fibrosis, pegozafermin, survodutide, tirzepatide, efruxifermin, liraglutide, vitamin E+pioglitazone, resmetirom, semaglutide, pioglitazone, denifanstat, and lanifibranor outperformed placebo, with pegozafermin (91.75), survodutide (90.87), and tirzepatide (84.70) ranking highest. Findings offer a current efficacy hierarchy to guide practice and trial design.

Reference: Souza M, Al-Sharif L, Antunes VLJ, Huang DQ, Loomba R. Comparison of pharmacological therapies in metabolic dysfunction-associated steatohepatitis for fibrosis regression and MASH resolution: Systematic review and network meta-analysis. Hepatology. 2025 Dec 1;82(6):1523-1533. doi: 10.1097/HEP.0000000000001254. Epub 2025 Feb 4. PMID: 39903735; PMCID: PMC12614381.

This AASLD-led update gives practical, clinician-facing guidance for using resmetirom—especially where the FDA label is less prescriptive—covering who to treat, concomitant therapy, and monitoring. It recommends treating adults with MASH and F2–F3 fibrosis, typically identified without routine biopsy using noninvasive liver disease assessments (NILDA)—preferably imaging-based VCTE/MRE. Treatment candidates also should have evidence of steatosis plus cardiometabolic risk factors and no competing causes (including higher alcohol intake). Blood-based tools can be used when imaging isn’t available, and a reasonably recent historical biopsy can still support decisions.

Management keeps lifestyle and metabolic risk control as the foundation and flags common real-world issues: drug interactions (CYP2C8—dose reduction with moderate inhibitors like clopidogrel) and statin dose caps when co-administered. Monitoring focuses on tolerability and safety (most AEs are diarrhea/nausea; rare hepatotoxicity warrants periodic hepatic panels) and on whether treatment is helping. At ~12 months, it suggests repeating the same NILDA and tracking ALT/fibrosis surrogates, using pragmatic thresholds (about 20% MRE or 25% VCTE change) to gauge improvement vs worsening. If signals are mixed, continuing therapy should be individualized, recognizing that stabilizing fibrosis may still be valuable.

Reference: Chen VL, Morgan TR, Rotman Y, et al. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD Practice Guidance. Hepatology. 2025 Jan 1;81(1):312-320. doi: 10.1097/HEP.0000000000001112. Epub 2024 Oct 18. Erratum in: Hepatology. 2025 Apr 1;81(4):E133. doi: 10.1097/HEP.0000000000001186. PMID: 39422487.

This practice recommendation updates 2023 AASLD guidance (NAFLD → MASLD) with implementable, semaglutide-specific direction on who to treat and how to monitor. It cites accelerated FDA approval (August 2025) of Wegovy (semaglutide 2.4 mg weekly) for MASH with F2–F3 fibrosis based on interim ESSENCE results. Those data showed higher rates of MASH resolution without fibrosis worsening (62.9% vs 34.3% placebo) and ≥1-stage fibrosis improvement without MASH worsening (36.8% vs 22.4%), with final approval pending long-term outcomes. Candidates should be identified mainly via noninvasive tests (e.g., VCTE, MRE, ELF) rather than biopsy, with added confirmation to exclude cirrhosis in borderline/high ranges.

Monitoring emphasizes tolerability and risk awareness. GI AEs (nausea, diarrhea, constipation, vomiting) are most common and usually mild/transient; education and gradual titration help persistence. Routine hepatic panels are generally only as clinically indicated, alongside vigilance for uncommon but important risks—dehydration-related acute kidney injury, symptomatic gallbladder disease, pancreatitis, thyroid C-cell tumor warning, retinopathy progression, and potential lean-mass loss. Lifestyle intervention remains foundational, and combination with resmetirom at 2.4 mg/week hasn’t been studied. Response is followed with trends in ALT and noninvasive tests (NITs)—improvement supports benefit; worsening raises concern—recognizing no NIT reliably predicts individual histologic response.

Reference: Bansal MB, Patton H, Morgan TR, et al. Semaglutide therapy for metabolic dysfunction-associated steatohepatitis: November 2025 updates to AASLD Practice Guidance. Hepatology. 2025 Nov 7. doi: 10.1097/HEP.0000000000001608. Epub ahead of print. PMID: 41201884.

In an ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled trial, investigators are studying once-weekly subcutaneous semaglutide (2.4 mg) as a potential therapy for metabolic dysfunction–associated steatohepatitis (MASH). A total of 1197 patients with biopsy-confirmed MASH and fibrosis stage 2 or 3 were randomized in a 2:1 ratio to semaglutide or placebo for a planned 240 weeks. This publication reports a prespecified interim analysis at Week 72 (part 1) from the first 800 enrolled patients, using two primary histologic endpoints: (1) resolution of steatohepatitis without worsening of fibrosis and (2) improvement in fibrosis without worsening of steatohepatitis.

At Week 72, semaglutide demonstrated statistically significant advantages over placebo on both primary endpoints. Resolution of steatohepatitis without fibrosis worsening occurred in 62.9% of semaglutide-treated patients vs 34.3% with placebo (estimated difference, 28.7 percentage points; 95% CI, 21.1 to 36.2; P<0.001). Fibrosis improvement without steatohepatitis worsening was observed in 36.8% vs 22.4%, respectively (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001). Secondary outcomes also favored semaglutide, including a higher rate of combined steatohepatitis resolution plus fibrosis reduction (32.7% vs 16.1%) and substantially greater mean weight loss (−10.5% vs −2.0%), while mean changes in bodily pain scores were not significantly different. Gastrointestinal adverse events were more common with semaglutide, consistent with the known tolerability profile of GLP-1 receptor agonists.

Reference: Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025 Jun 5;392(21):2089-2099. doi: 10.1056/NEJMoa2413258. Epub 2025 Apr 30. PMID: 40305708.

Researchers of this two-year randomized trial tested whether a hypocaloric Mediterranean-style dietary program—with or without structured physical activity—could reduce intrahepatic fat content (IFC) in adults (40-60 years) with obesity, metabolic syndrome, and MRI-confirmed metabolic-associated fatty liver disease (MAFLD). Researchers also evaluated whether changes in liver fat relate to kidney health and systemic oxidative/inflammatory status. Sixty-seven participants were randomized to one of three arms (conventional energy-restricted diet; Mediterranean diet with high meal frequency; Mediterranean diet plus interval training), all with an approximately 25% to 30% calorie reduction. A biomarker subgroup (n=40) was analyzed by IFC response after 24 months (responders vs non-responders).

Irrespective of assignment, participants who reduced IFC showed lower liver fat and stable liver stiffness, greater fitness, weight/body mass index loss, improved lipids, reduced liver enzymes, and lower ferritin and uric acid. They also had less oxidative stress and inflammation and better kidney indices. Non-responders tended toward higher liver stiffness, slightly higher diastolic blood pressure, compensatory rises in erythrocyte antioxidant enzymes, increased urinary cystatin C/creatinine, and worsening creatinine/Modification of Diet in Renal Disease. Overall, achieving liver-fat reduction with a Mediterranean-based lifestyle program was linked to favorable hepatic, cardiometabolic, inflammatory, and renal profiles. These results support a clinical connection between MAFLD and chronic kidney disease and the importance of kidney monitoring in MAFLD care.

Reference: Quetglas-Llabrés MM, Monserrat-Mesquida M, Bouzas C, et al. Effects of a Two-Year Lifestyle Intervention on Intrahepatic Fat Reduction and Renal Health: Mitigation of Inflammation and Oxidative Stress, a Randomized Trial. Antioxidants (Basel). 2024;13(7):754. doi: 10.3390/antiox13070754.

A diagnosis of metabolic-associated steatotic liver disease, or metabolic dysfunction–associated steatohepatitis, can feel overwhelming, but small, realistic changes add up. Researchers encourage patients to personalize goals and start where they are. For instance, adding about 2,500 steps per day is associated with an approximately 20% lower risk of disease progression. A Mediterranean-style eating pattern (fruits, vegetables, whole grains, lean proteins) with limited added sugars and processed foods is recommended, and up to three cups of black coffee daily may help. Alcohol should be used cautiously and avoided with advanced scarring or when fibrosis stage is uncertain. Dr. Jonathan Stine emphasizes that individualized plans tend to be more sustainable.

Sustainable habits matter: Patients should target 150 minutes per week of moderate activity, include simple resistance exercises, and split sessions into 10-minute bouts as needed. Trackers and apps can support gradual change. Starting with at least 500 steps per day builds momentum, and a 10% fitness improvement is associated with an approximately 15% lower mortality. Consistency beats perfection. Occasional indulgences can be followed by a reset the next day. Additional education and peer support can improve adherence over time.

Reference: Betel M, Stine J. Practical Lifestyle Tips for MASLD and MASH Patients. Fatty Liver Alliance. Published January 26, 2025. Accessed October 10, 2025. https://fattyliver.ca/blog/f/practical-lifestyle-tips-for-masld-and-mash-patients?blogcategory=Liver+Insights+2+for+Patients

The global rise in obesity has significantly increased the prevalence of non-alcoholic fatty liver disease (NAFLD), which can progress to severe conditions like nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Studies have shown that a weight reduction of 7% to 10% can resolve NASH and improve liver fibrosis. However, only a small percentage of patients achieve and maintain this weight loss with lifestyle changes alone. As a result, bariatric surgery has emerged as a viable treatment option for obese patients with NAFLD, leading to significant improvements in liver health and metabolic outcomes.

Bariatric surgery, particularly Roux-en-Y gastric bypass and sleeve gastrectomy, has been shown to induce long-term weight loss, improve liver function, and reduce the risk of cardiovascular disease and NAFLD-related HCC. These procedures also offer potential benefits for patients with compensated cirrhosis, although careful patient selection and multidisciplinary evaluation are crucial. Emerging endoscopic bariatric therapies show promise for treating NAFLD but require further research.

Reference: Geerts A, Lefere S. Bariatric surgery for non-alcoholic fatty liver disease: Indications and post-operative management. Clin Mol Hepatol. 2023 Feb;29(Suppl):S276-S285. doi: 10.3350/cmh.2022.0373. Epub 2022 Dec 22. PMID: 36545709; PMCID: PMC10029945.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease globally, and endoscopic sleeve gastroplasty (ESG) has emerged as a feasible and effective intervention for managing obesity. A systematic review and meta-analysis of four observational studies, including 175 patients, evaluated the impact of ESG on NAFLD and metabolic parameters 12 months post-procedure. The analysis revealed significant improvements in liver health, with reductions in hepatic steatosis index, NAFLD fibrosis score, and ALT levels. Additionally, patients experienced substantial weight loss, with a 17.28% decrease in total weight loss and a 47.97% reduction in excess weight loss.

The study also found that ESG led to a significant reduction in body mass index by 6.31 kg/m² and a decrease in HbA1c levels by 0.51%, indicating improved metabolic control in patients with NAFLD. These findings suggest that ESG not only aids in weight loss but also positively impacts liver function and metabolic health in individuals with NAFLD, making it a promising treatment option for this widespread condition.

Reference: Nunes BCM, de Moura DTH, Kum AST, et al. Impact of Endoscopic Sleeve Gastroplasty in Non-alcoholic Fatty Liver Disease: a Systematic Review and Meta-analysis. Obes Surg. 2023 Sep;33(9):2917-2926. doi: 10.1007/s11695-023-06747-4. Epub 2023 Aug 4. PMID: 37537506.

Non-alcoholic fatty liver disease (NAFLD) is characterized by ≥5% hepatic steatosis unrelated to alcohol or drug use, primarily driven by metabolic dysfunction, obesity, and type 2 diabetes. It ranges from simple steatosis to non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, and liver cancer, affecting 20% to 30% of the global population. Genetic factors like PNPLA3, TM6SF2, and MBOAT7 polymorphisms contribute to NAFLD risk. Dietary and environmental factors, along with inflammation and oxidative stress, also play key roles. Recent research emphasizes the gut microbiome’s importance in NAFLD progression, suggesting new treatments like probiotics, fecal microbiota transplantation, and dietary changes.

The gut-liver axis is crucial in NAFLD, as gut microbiome imbalances lead to increased intestinal permeability, liver inflammation, and fibrosis. Modifying the gut microbiome, particularly through bile acid alterations, presents a promising treatment pathway. Ursodeoxycholic acid, a secondary bile acid with anti-inflammatory and anti-fibrotic effects, has shown potential in animal studies for improving liver function and modulating the gut microbiome. However, human trials have yet to show consistent histological improvements, necessitating further research into UDCA and gut microbiome therapies for NAFLD.

Reference: Mao Q, Lin B, Zhang W, et al. Understanding the role of ursodeoxycholic acid and gut microbiome in non-alcoholic fatty liver disease: current evidence and perspectives. Front Pharmacol. 2024 Mar 21;15:1371574. doi: 10.3389/fphar.2024.1371574. PMID: 38576492; PMCID: PMC10991717.

The terms nonalcoholic fatty liver disease and nonalcoholic steatohepatitis have been replaced by metabolic-dysfunction-associated steatotic liver disease (MASLD) to reduce stigmatization. Defined by liver steatosis and at least one cardiometabolic risk factor like obesity or diabetes, MASLD is projected to affect over half of adults by 2040 due to the obesity pandemic. Around 20-30% of patients may progress to metabolic-dysfunction-associated steatohepatitis, which can lead to cirrhosis and liver cancer, placing a growing burden on healthcare systems.

MASLD is strongly associated with metabolic syndrome, with obesity, diabetes, and hypertension as key risk factors. Insulin resistance and metabolic abnormalities like increased free fatty acids contribute to liver inflammation and fibrosis. MASLD also elevates cardiovascular disease risk, making it crucial to address both liver and heart health. Lifestyle changes, including diet and exercise, have shown promise in improving liver function and metabolic health.

Reference: Yanai H, Adachi H, Hakoshima M, Iida S, Katsuyama H. Metabolic-Dysfunction-Associated Steatotic Liver Disease-Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Treatments. Int J Mol Sci. 2023 Oct 23;24(20):15473. doi: 10.3390/ijms242015473. PMID: 37895151; PMCID: PMC10607514.

Efruxifermin, an experimental drug mimicking fibroblast growth factor 21, is being investigated in phase 3 SYNCHRONY trials for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). The drug aims to target metabolic pathways to reverse liver scarring without worsening the condition. The SYNCHRONY trials evaluate efruxifermin’s safety and efficacy across various MASH fibrosis stages, including pre-cirrhotic and cirrhotic conditions. Previous phase 2b trials, like the HARMONY trial, demonstrated that efruxifermin effectively improved fibrosis in patients with pre-cirrhotic MASH without worsening the condition, with up to 75% of patients showing at least a 1-stage improvement in fibrosis.

Efruxifermin is being tested in three phase 3 SYNCHRONY trials, which include biopsy-confirmed pre-cirrhotic MASH (SYNCHRONY Histology), non-invasively diagnosed MASH or metabolic dysfunction-associated steatotic liver disease (SYNCHRONY Real-World), and compensated cirrhosis due to MASH (SYNCHRONY Outcomes). Early trials have shown promising results, with efruxifermin improving fibrosis in patients, particularly at higher doses, while being generally well-tolerated. These findings suggest that efruxifermin has significant potential in treating MASH and could reduce healthcare costs by potentially minimizing the need for liver biopsies.

Reference: McGovern G. Efruxifermin Demonstrates Potential in Treating Patients With MASH-Related Scarring or Cirrhosis. Pharmacy Times. Published February 5, 2025. Accessed March 18, 2025. https://www.pharmacytimes.com/view/efruxifermin-demonstrates-potential-in-treating-patients-with-mash-related-scarring-or-cirrhosis

Nonalcoholic steatohepatitis (NASH) is rapidly becoming the leading indication for liver transplantation in the US. However, patients with NASH face significant barriers to care, including challenges related to weight loss, which is often required for liver transplant eligibility. Unlike patients with alcohol-associated liver disease (ALD), who have access to multiple resources to promote sobriety, individuals with NASH lack validated, affordable weight loss programs. While weight loss is not a predictor of better post-transplant survival, it can exacerbate sarcopenia, a condition linked to poor outcomes. This highlights that weight loss should not be used as a requirement for liver transplant eligibility in patients with NASH.

Patients with NASH face higher waitlist mortality than those with ALD, despite similar post-transplant survival rates. Weight loss requirements for patients with NASH are misguided and may actually worsen outcomes by contributing to sarcopenia. Data show that patients with higher pretransplant BMI benefit more from transplantation, contradicting the belief that weight loss improves survival. Weight loss after transplant has been shown to have more benefits, and patients with NASH do not face a higher risk of graft loss compared to patients with ALD. As NASH becomes the leading cause for liver transplant, it is essential to prioritize patients with NASH and remove weight loss as a prerequisite for transplant eligibility, ensuring equity in access to care.

Reference: Manfready RA, Rzepczynski A, Janardhan SV. Which patient should be prioritized for liver transplant: NAFLD? Clin Liver Dis (Hoboken). 2024 Jun 7;23(1):e0163. doi: 10.1097/CLD.0000000000000163. PMID: 38860126; PMCID: PMC11164004.

This nationwide, population-based cross-sectional study aimed to assess the prevalence of liver steatosis and fibrosis in both the general population and high-risk groups in China, using data from over 5.7 million adults who underwent health check-ups between 2017 and 2022. Steatosis and fibrosis were evaluated via transient elastography, and the results were stratified by demographic and clinical risk factors. A mixed effect regression model was used to identify independent predictors associated with liver abnormalities.

The study found a high prevalence of liver steatosis (44.39%), severe steatosis (10.57%), advanced fibrosis (2.85%), and cirrhosis (0.87%). Males and individuals with obesity, diabetes, hypertension, metabolic syndrome, or elevated liver enzymes had significantly higher rates of both steatosis and fibrosis. Fatty liver, decreased albumin or platelet counts, and hepatitis B infection were also linked to higher fibrosis rates. Most cardiovascular and chronic liver disease risk factors were independent predictors of steatosis and fibrosis, except dyslipidemia for fibrosis. These findings underscore the need for routine screening and risk stratification in high-risk populations, particularly those with diabetes, to better manage the growing burden of liver disease in China.

Reference: Man S, Deng Y, Ma Y, et al. Prevalence of Liver Steatosis and Fibrosis in the General Population and Various High-Risk Populations: A Nationwide Study With 5.7 Million Adults in China. Gastroenterology. 2023 Oct;165(4):1025-1040. doi: 10.1053/j.gastro.2023.05.053. Epub 2023 Jun 26. PMID: 37380136.