The role of thyroid hormone beta 1 receptor (THRβ1) in metabolic dysfunction associated steatohepatitis (MASH): from dysregulation to therapeutic target.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is still one of the most common chronic liver diseases worldwide. The build-up of triglycerides in the liver is a key feature of MASLD and can lead to oxidative stress and inflammation, thereby progressing to metabolic dysfunction-associated steatohepatitis (MASH). The recent FDA approval of Resmetirom (Rezdiffra) for adults with non-cirrhotic MASH and moderate-to-advanced liver fibrosis marks a significant step forward in treatment and has once again sparked interest in THRβ1 as a target for metabolic therapies. THRβ1 is a major regulator of hepatic metabolism, influencing fatty acid oxidation, cholesterol homeostasis, mitochondrial function, and other pathways that maintain the liver's lipid balance. In MASH, disruption of THRβ1 signaling, including changes in receptor expression and the local availability of thyroid hormone, may contribute to lipid accumulation in the liver, the development of metabolic dysfunction, inflammation, and disease progression. As a result, liver-selective activation of THRβ1 has become a promising therapeutic approach for restoring metabolic homeostasis while avoiding the systemic effects associated with thyroid hormone. Clinical and preclinical studies involving Resmetirom and other thyromimetics, such as VK2809, ASC41, and TERN-501, have shown beneficial effects on hepatic steatosis, lipid metabolism, and the histological features of MASH. This review offers a detailed look at the structure of THRβ1, how ligands bind to it, the mechanisms of its transcriptional regulation, and its roles in the metabolism of lipids, cholesterol, glucose, and mitochondria in the liver, before going on to analyze the dysregulation of THRβ1 in MASH and the pharmacological and structural reasons for the selectivity of THRβ1 agonists. The review also examines Resmetirom and other emerging thyromimetics, liver-targeted drug-design strategies, combination therapies, and unresolved mechanistic questions, highlighting the potential to develop next-generation therapies directed at THRβ1 for the treatment of MASH.