Drug Development for MASH-Related Compensated Cirrhosis: Past, Present and Future.

Compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis (MASH) represents a major unmet need in hepatology, with no approved treatment to date. Compared with non-cirrhotic MASH, compensated cirrhosis is characterized by concurrent metabolic dysfunction, persistent inflammation, stabilized fibrosis and portal hypertension, making therapeutic development substantially more challenging. In recent years, several agents initially developed for non-cirrhotic disease have advanced into compensated MASH-related cirrhosis, including fibroblast growth factor 21 analogues, glucagon-like peptide-1 receptor/glucagon receptor dual agonists, thyroid hormone receptor-beta agonists and other antifibrotic approaches. Among these, fibroblast growth factor 21 analogues have shown the most encouraging efficacy signals. However, most candidates have not demonstrated clear histological or clinical benefit in this population. The predominance of negative trials suggests that limited progress reflects not only insufficient drug efficacy, but also disease complexity, marked patient heterogeneity and limitations of current endpoint frameworks. This review summarizes recent progress in drug development for compensated MASH-related cirrhosis, evaluates the efficacy and safety of major investigational agents, and discusses key barriers to development, including endpoint limitations, patient stratification and trial design. It also outlines future directions, including precision stratification, composite endpoints, noninvasive assessment tools, combination strategies and earlier screening and intervention.