The metabolic dysfunction-associated steatohepatitis (MASH) drug resmetirom exhibits broad nuclear receptor activity with minimal functional impact

TL;DR

Resmetirom, a drug approved for MASH, activates several nuclear receptors but primarily affects the thyroid hormone receptor β, maintaining its therapeutic effectiveness.

Contribution

The study reveals resmetirom's broad nuclear receptor activity but confirms its functional dominance through in vitro experiments.

Findings

Resmetirom binds to multiple nuclear receptors like CAR, RORs, and HNF4α.

THRβ modulation is functionally dominant despite off-target effects.

The drug's therapeutic efficacy for MASH remains intact.

Abstract

In 2024, the FDA granted approval for resmetirom, a selective but moderately potent agonist of the thyroid hormone receptor (THR) β, marking the first drug for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) in the US. Given the absence of selectivity data, we conducted a comprehensive screening against other nuclear receptors implicated in metabolic regulation, in addition to THRβ. Reporter gene assays revealed that resmetirom also binds several off-target nuclear receptors, including constitutive androstane receptor (CAR), retinoic acid receptor-related orphan receptors (RORs), and hepatocyte nuclear factor 4α (HNF4α). However, subsequent in vitro experiments, designed to better recapitulate physiological conditions, showed that THRβ modulation is functionally dominant. These preliminary findings suggest that pharmacotherapeutic efficacy of resmetirom remains intact despite the identified off-target effects, supporting its clinical application in the treatment of MASH.

The online version contains supplementary material available at 10.1038/s41598-026-37494-y.

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