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Updated: May 17, 2026
Drug Repurposing Hypothesis Generation Using the "RE:fine Drugs" System
Published on: December 11, 2016
Repurposing Resmetirom to Suppress MASLD/MASH-HCC in the Dysmetabolic Era
Amedeo Lonardo1, Ming-Hua Zheng2, Ralf Weiskirchen3
1Independent Researcher, Modena, Italy. a.lonardo@libero.it.
Abstract:
Metabolic disorders are risk factors for hepatocellular carcinoma (HCC) through complex proinflammatory, molecular, and cellular processes within a systemic dysmetabolic milieu. Despite significant advancements in the last two decades, HCC remains a challenging condition to treat. Resmetirom is a liver‑directed, selective THR‑β agonist that enhances mitochondrial β-oxidation, reduces de novo lipogenesis, improves lipid and cholesterol homeostasis, and, in preclinical HCC associated with metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH-HCC) models, attenuates midkine/lipoprotein receptor-related protein 1 (MDK/LRP1)-mediated immunosuppressive crosstalk. In this article, we discuss the possibility and rationale for repurposing Resmetirom, which has recently been approved for the treatment of MASH, to potentially suppress MASLD/MASH-HCC. This discussion considers the evolving epidemiology of HCC, the ongoing challenges in HCC treatment, and the intricate connection between thyroid hormone signaling, MASLD, and HCC.
Insights
Resmetirom, a MASH treatment, may suppress metabolic dysfunction-associated steatotic liver disease/steatohepatitis-hepatocellular carcinoma (MASLD/MASH-HCC). Its thyroid hormone receptor beta (THR-β) agonism targets key pathways in preclinical models.
Area of Science:
- Hepatology and Oncology
- Endocrinology and Metabolic Diseases
Background:
- Metabolic disorders significantly increase hepatocellular carcinoma (HCC) risk via complex inflammatory and molecular pathways.
- Despite advancements, HCC remains a difficult-to-treat malignancy, necessitating novel therapeutic strategies.
- Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are increasingly linked to HCC development.
Purpose of the Study:
- To explore the rationale and potential for repurposing Resmetirom, a selective thyroid hormone receptor beta (THR-β) agonist, for treating MASLD/MASH-associated HCC (MASLD/MASH-HCC).
- To discuss the therapeutic implications of Resmetirom's known mechanisms in the context of HCC suppression.
Main Methods:
- Review of existing literature on metabolic disorders, HCC pathogenesis, and Resmetirom's pharmacological profile.
- Analysis of Resmetirom's preclinical effects on pathways relevant to MASLD/MASH-HCC, including mitochondrial β-oxidation, lipogenesis, and MDK/LRP1 signaling.
- Consideration of thyroid hormone signaling's role in MASLD and HCC.
Main Results:
- Resmetirom enhances mitochondrial β-oxidation and reduces de novo lipogenesis, improving lipid homeostasis.
- Preclinical MASLD/MASH-HCC models show Resmetirom attenuates MDK/LRP1-mediated immunosuppressive crosstalk.
- Resmetirom's liver-directed action and THR-β selectivity offer a targeted approach.
Conclusions:
- Resmetirom's established efficacy in MASH and its demonstrated preclinical anti-tumorigenic effects in MASLD/MASH-HCC models support its potential repurposing.
- Targeting thyroid hormone signaling with Resmetirom presents a promising avenue for suppressing MASLD/MASH-HCC, addressing a critical unmet need in oncology.
