Repurposing Resmetirom to Suppress MASLD/MASH-HCC in the Dysmetabolic Era

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.