Combination Therapies for MASH: JOH, April 2026

Introduction

Metabolically–dysfunction–associated steatohepatitis (MASH) is a complex, multisystem disease driven by obesity, insulin resistance, lipotoxicity, inflammation, and fibrosis. Traditional single-drug therapies have shown limited success because they target only one pathway in a highly heterogeneous disease. As a result, there is a growing shift toward combination therapies that address multiple pathogenic mechanisms simultaneously, aiming for more effective disease modification and improved long-term outcomes.

Problem Statement

Monotherapy in MASH often leads to partial improvements in liver histology and metabolic parameters, with inconsistent effects on fibrosis regression and systemic disease burden. Given the multifactorial pathogenesis of MASH, there is a critical need for therapeutic strategies that can target both hepatic injury and systemic metabolic dysfunction while maintaining safety and tolerability.

Summary

This review highlights the emerging role of combination therapies as a paradigm shift in MASH management. Liver-directed combinations such as thyroid hormone receptor-β agonists with ACC inhibitors or PPAR agonists aim to directly improve steatosis and fibrosis. Systemic–hepatic combinations, including GLP-1 receptor agonists with FGF-21 analogues or THR-β agonists, address both metabolic dysfunction and liver disease. Novel dual or complementary drug pairings may also enhance efficacy while minimizing adverse effects. Overall, combination strategies offer a more comprehensive and personalized approach, with the potential to achieve meaningful fibrosis regression and