Effects of Resmetirom on Resistance to Thyroid Hormone Receptor Mutants: Potential Basis for Therapeutic Applications

Resistance to thyroid hormone-β (RTHβ) is caused by mutations in thyroid hormone receptors (TRs), with palpitations, tachycardia, and/or goiter being the most frequently reported clinical features. In recent years, several synthetic thyromimetics have been developed to target mutations associated with RTHβ. Resmetirom, which was granted an accelerated approval by the U.S. Food and Drug Administration, is a TRβ-agonist for the first line therapy for metabolic dysfunction-associated steatohepatitis. This study aimed to evaluate the potential mechanisms of action of resmetirom on RTHβ through co-factors and association with clinical manifestations. We selected cases from 13 clinical records based on recently reported domestic cases in Japan. Based on these clinical reports, we conducted screenings using clinical symptoms, laboratory findings, and mutation data. We attempted to unveil the interaction between 26 RTHβ mutants and resmetirom focusing on recruitment of co-factors. Among the 26 probands, dominant-negative effects (DNE) were identified in 12 mutant TRs (48.5 ± 11.8%). Resmetirom was involved in the recruitment of the co-activators, steroid receptor coactivator-1 and glucocorticoid receptor-interacting protein-1, as well as the co-repressors (CoRs), nuclear-CoR and silencing mediator of retinoic acid and TR. Co-factor recruitment by resmetirom was detected in all mutants. In eight patients with DNE, an association between transcriptional activity and clinical symptoms was observed, which were the reasons for clinical investigation. Notably, in the helix-12 mutant-P453, mild induction of DNE was associated with the recruitment of CoRs, suggesting that resmetirom may be effective in alleviating subjective symptoms in mutants with attenuated DNE located in helix-12.