Resmetirom and thyroid hormone receptor-targeted treatment for metabolic dysfunction-associated steatotic liver...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a rapidly increasing chronic disease worldwide, particularly among patients with type 2 diabetes. Its severe form, metabolic dysfunction-associated steatohepatitis (MASH), is also on the rise. The treatment of MASLD and MASH poses significant challenges. Thyroid hormones and their receptors (TR) agonists, especially resmetirom, have shown potential in improving metabolism and reducing liver inflammation. Thyroid hormones play a crucial role in regulating metabolism and maintaining physiological balance. However, in patients with MASLD, there is a reduced conversion of 3,3',5,5'-tetraiodo-L-thyronine (T₄) to biologically active 3,5,3'-triiodo-L-thyronine (T₃), resulting in decreased T₃ levels and impaired hepatic TR signaling. This hormonal imbalance is associated with disrupted hepatic lipid metabolism. Resmetirom, an oral selective TR agonist that specifically targets hepatocytes, was approved by the Food and Drug Administration (FDA) in March 2024 for the treatment of moderate to severe liver fibrosis in non-cirrhotic adults with MASH. This approval was based on the results of the MAESTRO clinical program, which includes multiple-stage research designs such as the MAESTRO-NASH, MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, and MAESTRO-NASH-OUTCOMES, aims to evaluate the efficacy and safety of resmetirom in different populations of MASH patient. Although the approval of resmetirom represents a significant milestone in the treatment of MAFLD and MASH, many questions remain regarding its long-term effectiveness and impact on clinical outcomes. Ongoing research, particularly through the MAESTRO program, holds promise for providing additional insights into the long-term management of MASLD using resmetirom and other similar medications.