Emerging treatment options for metabolic dysfunction-associated steatotic liver disease and its related liver diseases

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading and increasingly prevalent chronic liver disease, affecting approximately 1.2 billion people worldwide. It can be triggered by genetic susceptibility factors and dietary habits. MASLD is characterized by liver fat accumulation, inflammation, cell death, and varying degrees of liver fibrosis. Without appropriate treatment and management, the progressive form of MASLD, metabolic dysfunction-associated steatohepatitis (MASH), can lead to liver cirrhosis and hepatocellular carcinoma. Currently, there are two United States Food and Drug Administration approved drugs for the treatment of MASH with moderate to advanced liver fibrosis: resmetirom, an oral agonist of thyroid hormone receptor-β, and semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist. Ongoing clinical trials indicate that many emerging therapies show promising efficacy and potential applications for MASLD and MASH treatment, including dual glucagon receptor and GLP-1 receptor agonists, fibroblast growth factor analogues, and pan-peroxisome proliferator-activated receptor agonists. In this review, we summarize the pathogenesis of MASLD and MASH and examine current clinical trials for their treatment, with a focus on pharmaceutical therapies, dietary modifications, and natural products. Additionally, repurposing currently approved drugs for metabolic diseases, as well as combination therapies, may provide effective treatment strategies for MASLD and MASH.

Keywords: Metabolic dysfunction-associated steatotic liver disease; Metabolic dysfunction-associated steatohepatitis; Clinical trials; Molecular mechanisms; Treatments; Therapeutic strategies

Core Tip: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common type of chronic liver disease, affecting more than a quarter of the global population. MASLD is driven by many factors, including dietary and genetic factors. Without effective treatment, MASLD can lead to liver cirrhosis and cancer. Currently, treatment options for MASLD and metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of MASLD, are limited. Ongoing clinical trials suggest that drug repurposing for metabolic disorders, dietary modifications, exercise, natural products, and combination therapies offer promising strategies for the management and treatment of MASLD and MASH.