Thyroid hormone receptor (THR) is a member of the nuclear receptor superfamily that shuttles between the cytosol and nucleus. THRs are ligand-dependent transcription factors that mediate the biological activities of thyroid hormone (T3). THRs are zinc finger transcription factors in the erbA superfamily that bind DNA at specific response element sequences (thyroid hormone response elements, TREs) and activate gene expression in response to thyroid hormone (T3). Moreover, THRs can bind DNA as monomers, homodimers, or heterodimers with another erbA superfamily member, the retinoid X receptor (RXR).

The major isoforms of THRs are THR-α1, THR-α2, THR-β1, and THR-β2. THRs mediate the pleiotropic activities of the thyroid hormone (T3) in growth, development, and differentiation and in maintaining metabolic homeostasis. Activation of hepatic THR-β plays an important role in systemic lipid lowering, increased bile acid synthesis, and fat oxidation. In patients with non-alcoholic steatohepatitis (NASH), treatment with THR-β agonists decreased hepatic steatosis and circulating lipids, and induced resolution of NASH.

Resmetirom (MGL-3196; VIA-3196) is a selective and orally active THR-β agonist.

THR-β is responsible for regulating metabolic pathways in the liver and is frequently impaired in NASH. Patients with NASH have reduced levels of thyroid hormone activity in the liver with resultant impaired hepatic function. Resmetirom is a selective and orally active THR-β agonist. Resmetirom is 28-fold selective for THR-β over THR-α in a functional assay. Meanwhile, Resmetirom exhibits good exposures and reasonable oral bioavailability in rats. In animals treated with Resmetirom there is a reduction in cholesterol and in liver size, which is secondary to reduction of liver TG. There is no effect on bone mineral density (BMD) or heart or kidney size in Resmetirom treated animals. Therefore, Resmetirom has potential for the research of metabolic dysfunction-associated steatohepatitis (MASH), a more advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD) .


[1] Kannt A, et, al. Br J Pharmacol. 2021 Jun;178(12):2412-2423.

[2] Harrison SA, et, al. Nat Med. 2023 Nov;29(11):2919-2928.