Pipeline of New Drug Treatment for Non-alcoholic Fatty Liver Disease/Metabolic Dysfunction-associated Steatotic Liver Disease.

Abstract

Given the global prevalence and rising incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), the absence of licensed medications is striking. A deeper understanding of the heterogeneous nature of MASLD has recently contributed to the discovery of novel groups of agents and the potential repurposing of currently available medications. MASLD therapies center on four major pathways. Considering the close relationship between MASLD and type 2 diabetes, the first approach involves antidiabetic medications, including incretins, thiazolidinedione insulin sensitizers, and sodium-glucose cotransporter 2 inhibitors. The second approach targets hepatic lipid accumulation and the resultant metabolic stress. Agents in this group include peroxisome proliferator-activated receptor agonists (e.g., pioglitazone, elafibranor, saroglitazar), bile acid-farnesoid X receptor axis regulators (obeticholic acid), de novo lipogenesis inhibitors (aramchol, NDI-010976), and fibroblast growth factor 21/19 analogs. The third approach focuses on targeting oxidative stress, inflammation, and fibrosis. Agents in this group include antioxidants (vitamin E), tumor necrosis factor α pathway regulators (emricasan, pentoxifylline, ZSP1601), and immune modulators (cenicriviroc, belapectin). The final group targets the gut (IMM-124e, solithromycin). Combination therapies targeting different pathogenetic pathways may provide an alternative to MASLD treatment with higher efficacy and fewer side effects. This review aimed to provide an update on these medications.