Targeting THR-β for MASLD: Mechanisms and Drug Development

Yunlong Hua,1,* Yang Liu,2,* Lianjun Xing,3 Xiao Yu,3 Peiyong Zheng,1 Lili Yang,1 Haiyan Song1 1Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China; 2School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 3Department II of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haiyan Song, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, People’s Republic of China, Email [email protected] Lili Yang, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, People’s Republic of China, Email [email protected]: 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.Keywords: thyroid hormone, thyroid hormone receptor-β, agonist, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis