Effects of resmetirom on the lipotoxicity of hepatoma cells

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common chronic liver diseases and its prevalence is steadily increasing. To date, there is no effective drug therapy available. The pathogenesis of MASLD is described by the “multiple hit” theory, in which lipotoxicity caused by the accumulation of free fatty acids (FFA) and their toxic metabolites, cell stress, and inflammatory processes in the liver play a central role, making it susceptible to further damaging factors. Thyroid hormones (TH) and their interactions with the corresponding receptors are important modulators of metabolism. Among other things, they influence cholesterol levels and FFA content. Disruptions or limitations in the TH-signaling pathway can contribute to the progression of chronic liver diseases, including liver fibrosis. The selective THR-β agonist resmetirom is now approved for the treatment of MASH with liver fibrosis. In this study, we investigated the influence of resmetirom on lipotoxicity in HepG2 and Huh7 cells under culture conditions. The cells were incubated with FFA or palmitic acid (PA), with and without the addition of resmetirom, for 24 or 48 hours. Subsequently, the expression of death receptors, pro- and anti-apoptotic genes was analyzed using quantitative real-time PCR (qRT-PCR). We were able to show that the expression of the death receptors DR4, DR5, and TNFR1, as well as the pro-apoptotic genes PUMA and Bax, increased with treatment with FFA or PA, but decreased in combination with resmetirom. In conclusion, there is evidence that treatment with resmetirom can reduce lipotoxicity in human cell lines. Publication History Article published online: 26 January 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany