Thyroid hormone receptor-β analogues for the treatment of metabolic dysfunction-associated steatohepatitis (MASH)

Abstract

The association between suboptimal thyroid function ((sub)clinical hypothyroidism or low-normal thyroid function) and the metabolic syndrome and MASLD (metabolic dysfunction-associated steatotic liver disease) has been clearly established. Furthermore, in MASLD, intracellular thyroid hormone concentrations are low and the activation of the thyroid hormone receptor (THR) is reduced. Administration of thyroid hormone has been shown to reduce liver triglycerides by stimulating fatty acid disposal through lipophagy and beta-oxidation, and to lower LDL-cholesterol. As thyroid hormone exerts its effects in many different organs, including the heart and bone, several drug candidates have been developed as selective thyromimetics for the THR-β nuclear receptor with potent and liver-targeted activity. Importantly, these compounds have reduced affinity for the THR-α nuclear receptor and tissue distribution profiles that differ from endogenous thyroid hormones, thereby reducing unwanted cardiovascular side effects. The most advanced compound, resmetirom, is an oral drug that demonstrated, in a large phase III trial in patients with MASH (metabolic dysfunction-associated steatohepatitis), the ability to reduce liver fat, decrease aminotransferase levels and improve atherogenic dyslipidaemia with a good tolerability profile. This translated into histological improvement that led to accelerated approval of this drug for active fibrotic steatohepatitis, a milestone achievement as a first MASH drug.