Medication Review Video Module: What is Resmetirom and how does it work to treat MASH?

Thank you to Madrigal for your support of this Medication Review Video Module.

In this Medication Review Video Module, Robin Soto, NP, from UC San Diego Health Hepatology, provides an in-depth look at the mechanism of action of Resmetirom, the first and only FDA-approved drug for the treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH) in adults with F2, F3, or mild to moderate fibrosis.

Resmetirom is an oral, liver-directed, beta-selective thyroid hormone receptor agonist (THR-β agonist). In MASH, the accumulation of lipotoxic lipids leads to hepatocyte injury, inflammation, and hepatic stellate cell activation, resulting in progressive fibrosis and an increased risk of cirrhosis and hepatocellular carcinoma (HCC). By activating THR-β receptors primarily in the liver, Resmetirom reduces fat accumulation, enhances fatty acid oxidation, and lowers lipotoxicity, helping to slow disease progression.

Resmetirom works by regulating lipid metabolism, enhancing cholesterol conversion, and improving mitochondrial health. It upregulates genes involved in fatty acid oxidation, which helps reduce intrahepatic fat accumulation and improve overall lipid profiles. Additionally, Resmetirom increases the expression of bile acid synthesis enzymes, promoting cholesterol conversion to bile acids, which assists in lowering excess cholesterol in the liver.

Beyond its role in metabolism, Resmetirom enhances mitochondrial biogenesis and removes unhealthy mitochondria, increasing the liver's ability to metabolize free fatty acids. By reducing hepatic stellate cell activation, Resmetirom also decreases collagen deposition, which helps slow the progression of fibrosis and reduces inflammation associated with MASH.

Unlike systemic thyroid hormone therapies, Resmetirom selectively targets the liver, minimizing systemic thyroid-related side effects and making it a safe and effective treatment option for MASH.

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