Therapeutic landscape evolution for steatotic liver disease: from lifestyle interventions to precision pharmacotherapy.

Abstract

Steatotic liver disease (SLD) is a growing global epidemic, with metabolic dysfunction-associated steatotic liver disease now the most common chronic liver disease worldwide and closely linked to adverse cardiovascular outcomes. Lifestyle modification remains the cornerstone of management, with the Mediterranean diet as the preferred dietary intervention and emerging evidence supporting additional dietary and exercise strategies. Pharmacotherapy has advanced rapidly in recent years, with two U.S. Food and Drug Administration-approved options, resmetirom and semaglutide, for noncirrhotic metabolic dysfunction-associated steatohepatitis with moderate-to-advanced fibrosis, alongside multiple agents in development targeting different disease mechanisms. In metabolic dysfunction- and alcohol-associated liver disease, evidence remains limited, but management essentially focuses on alcohol cessation and optimization of cardiometabolic risk factors, with resmetirom, incretin-based therapies, and fibroblast growth factor-21 analogues representing promising therapeutic agents that have yet to be fully evaluated in clinical trials. The field is increasingly moving toward a precision medicine paradigm integrating pharmacologic and lifestyle interventions, tailored to disease phenotype, genetic risk, and gut microbiome. Key challenges include heterogeneity in treatment response, assessment of alcohol intake, and real-world implementation barriers. This review summarizes current and emerging therapies and highlights the role of precision medicine in advancing individualized care across the SLD spectrum.