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

Annette Kärcher, Laura Isigkeit, Nils Christiaan Bandomir, Manfred Schubert-Zsilavecz, Pascal Heitel

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Article in Scientific reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

5 authors.

Annette KärcherGoethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-Von-Laue-Str. 9, 60438, Frankfurt, Germany.

Laura IsigkeitGoethe University Frankfurt, Institute of Pharmacology & Clinical Pharmacy, Max-Von-Laue-Str. 9, 60438, Frankfurt, Germany.

Nils Christiaan BandomirGoethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-Von-Laue-Str. 9, 60438, Frankfurt, Germany.

Manfred Schubert-ZsilaveczGoethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-Von-Laue-Str. 9, 60438, Frankfurt, Germany.

Pascal HeitelGoethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-Von-Laue-Str. 9, 60438, Frankfurt, Germany. heitel@pharmchem.uni-frankfurt.de.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Fatty LiverReceptors, Cytoplasmic and NuclearAnimalsConstitutive Androstane ReceptorHumansThyroid Hormone Receptors betaConstitutive Androstane ReceptorReceptors, Cytoplasmic and NuclearThyroid Hormone Receptors betaMetabolic syndromeNuclear receptor modulatorReporter gene assayTarget gene expressionThyroid hormone receptor β

Identifiers

PMID41611794

DOI10.1038/s41598-026-37494-y

PMCPMC12855932

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.