Resmetirom attenuates atherosclerosis-associated dyslipidemia and vascular inflammation in high-fat diet-fed ApoE−/− mice

Background Atherosclerosis is driven by interacting lipid and inflammatory pathways. There remains a pressing clinical need for drugs that exert both lipid-lowering and vascular anti-inflammatory effects. Studies have suggested that thyroid hormone receptor β (THR-β) agonists can alleviate atherosclerosis while avoiding the cardiotoxic adverse effects associated with thyroid hormone. Resmetirom is an oral, once-daily, liver-targeted selective THR-β agonist. It has attracted attention for improving lipid metabolism, yet its effects on vascular inflammatory phenotypes remain poorly clarified. We investigated the effects of resmetirom on atherosclerosis-associated dyslipidemia, plaque burden and vascular inflammatory phenotypes. Methods Apolipoprotein E-deficient (ApoE - / - ) mice fed a high-fat diet (HFD) for 8 weeks were randomized to vehicle, low-dose (3 mg/kg/day), or high-dose (10 mg/kg/day) resmetirom for eight weeks ( n = 10 per group). Serum lipids, inflammatory cytokines, aortic plaque morphology, NLRP3 inflammasome signaling, NF-κB activation, oxidative stress, and macrophage polarization were analyzed by one-way ANOVA with Tukey post hoc testing; dose-response regression was performed across disease-bearing groups. Results Resmetirom treatment reduced aortic plaque burden, corrected atherogenic dyslipidemia, and suppressed aortic NLRP3 and caspase-1 expression in a dose-dependent manner. High-dose resmetirom lowered low-density lipoprotein cholesterol (LDL-C) by 39.48%, and reduced aortic lipid accumulation on Oil Red O staining compared to model controls. Additionally, it suppressed interleukin-1β (IL-1β) by 59.28%; Western blotting showed lower p-p65/total p65 ratio and higher IκBα/GAPDH abundance. Flow-cytometric ROS intensity decreased by 35.56%, and the M1/M2 macrophage ratio decreased by 72.81%. Exploratory cross-assay analyses showed coherent associations among systemic cytokines and aortic NF-κB/ROS/macrophage readouts. Conclusions Resmetirom attenuated atherosclerosis-associated dyslipidemia, plaque burden and vascular inflammation in HFD ApoE −/− mice. The data support an association between resmetirom treatment and suppression of the NF-κB/ROS-NLRP3 inflammatory phenotype, warranting mechanistic validation in models with direct pathway perturbation. These findings support its translational potential in atherosclerotic cardiovascular disease.