Targeting THR-β for MASLD: Mechanisms and Drug Development

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver disease worldwide, but there has long been a lack of effective therapeutic drugs. Thyroid hormone (TH) and its receptor THR-β play pivotal roles in hepatic metabolism, positioning THR-β as a promising therapeutic target for MASLD. Notably, Resmetirom, a selective THR-β agonist, gained FDA approval in 2024 for MASLD treatment, and several other THR-β agonists are currently undergoing preclinical or clinical studies. While these agents demonstrate effective in alleviating hepatic steatosis, inflammation, and fibrosis in MASLD, the disease heterogeneity and drugs’ adverse reactions remain key challenges. Therefore, further research is necessary to comprehensively assess their clinical efficacy and safety. This review summarizes the mechanisms by which TH/THR-β influences MASLD and recent advances in THR-β-targeted pharmacotherapy, aiming to enhance understanding of its therapeutic potential and promote drug development and clinical applications.