Editorial: Combination Therapies for <scp>MASH</scp> : A Step Forward or More Complexity?

Metabolic dysfunction–associated steatohepatitis (MASH) has become a growing clinical and public health challenge as obesity and metabolic disease rise worldwide [1]. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) and resmetirom have been FDA-approved and shown to improve liver histology, their effects are often limited, particularly in patients with advanced fibrosis [2]. These highlight the need for strategies to address the multiple interacting pathways involved in MASH. Combination therapy has gained increasing attention, with numerous early-phase clinical trials exploring agents with complementary mechanisms [3]. A recent phase 2 trial in MASH patients demonstrated that LYS006 combined with tropifexor was well tolerated and resulted in greater reductions in ALT and liver fat compared with monotherapy [4]. Such combinations may provide additive or synergistic benefits, potentially resulting in greater improvements in steatosis, inflammation, and fibrosis compared with monotherapy. To realise these benefits safely and effectively, several key considerations must guide clinical trial design and implementation [5]. First, combining therapies might increase the risk of overlapping adverse effects, including gastrointestinal symptoms, pruritus, or dyslipidemia. Proactive monitoring, stepwise dose escalation, and predefined stopping rules are essential to minimise harm and maintain adherence. Even minor tolerability issues in real-world practice can significantly reduce long-term compliance, thus limiting treatment effectiveness [6]. Second, combination therapies must provide benefits beyond those achieved by each agent alone, as individual drugs already improve liver histology and metabolic outcomes in MASH. Such combinations should be selected deliberately for their potential to deliver meaningful incremental effects, rather than being combined arbitrarily. Rigorous head-to-head clinical trials are required to confirm that these regimens offer additional efficacy and maintain safety in MASH patients. Third, combination therapy is likely to be most beneficial in selected patient populations rather than applied universally. MASH patients exhibit substantial heterogeneity in fibrosis stage, metabolic profile, comorbidities, and prior therapy response, all of which influence the efficacy and safety of combination regimens [7]. Combination regimens may be tailored to specific patient populations, serving as adjunct therapy for inadequate monotherapy responders or as early intensive treatment for those with advanced fibrosis or severe metabolic dysfunction. Fourth, MASH drug development should not be limited to liver biopsy evaluation [8]. Although improvements in liver fat or fibrosis are encouraging, potential cardiovascular and other extrahepatic risks still need careful consideration [9]. Long-term trials and real-world studies are needed to assess both liver-specific benefits and broader clinical outcomes. Fifth, the complexity and cost of combination therapies are important considerations [10]. Regimens involving multiple agents can increase pill burden, require dose modifications, complicate dosing schedules, and cause even minor adverse effects, all of which may reduce long-term adherence. In addition, increased costs may constrain their practical use. In summary, combination therapy offers a promising strategy for clinical trials in MASH, addressing its multifactorial pathophysiology. Careful selection of complementary agents, targeted patient populations, and integrated hepatic and systemic endpoints may enhance the likelihood of demonstrating meaningful and durable benefits. As evidence from ongoing clinical trials and real-world studies accumulates, combination approaches could establish a new paradigm for precision-guided management of MASH. Xiao-Dong Zhou: writing – original draft, writing – review and editing. Yusuf Yilmaz: writing – review and editing. Mazen Noureddin: writing – review and editing. Hung N. Luu: writing – review and editing. Ming-Hua Zheng: conceptualisation, funding acquisition, writing – review and editing, resources, supervision. The authors have nothing to report. Ming-Hua Zheng serves as a speaker for AstraZeneca, Hisky Medical Technologies and Novo Nordisk; as a consultant for Boehringer Ingelheim and Eieling Technology; and has received consulting fees from Boehringer Ingelheim. Yusuf Yilmaz received personal consultancy fees from Novo Nordisk and Zydus. Mazen Noureddin advises and received grants from GlaxoSmithKline, Madrigal, Novo Nordisk, Takeda and Terns. He advises and owns stock in CytoDyn. He advises 89BIO, Altimmune, Boehringer Ingelheim, Merck and Perspectum. He received grants from Allergan, Akero, Bristol Myers Squibb, Conatus, Corcept, Enanta, Galectin, GENFIT, Gilead, Novartis, Shire, Viking and Zydus. He owns stock in ChronWell and Rivus. This article is linked to Frias et al. papers. To view this article, visit https://doi.org/10.1111/apt.70475 and https://doi.org/10.1111/apt.70510. The authors have nothing to report.