Resmetirom Attenuates Atherosclerosis in ApoE ⁻/⁻ Mice by Suppressing the NF- κB/ROS–NLRP3 Inflammasome Axis

Atherosclerosis is a chronic inflammatory vascular disease in which the NLRP3 inflammasome and NF-κB signaling play central pathogenic roles. Resmetirom, a liver-selective thyroid hormone receptor β (THR-β) agonist approved for metabolic dysfunction-associated steatohepatitis (MASH), exhibits potent lipid-lowering effects, yet its anti-inflammatory actions in atherosclerosis remain unexplored. We aimed to investigate whether resmetirom attenuates atherogenesis through suppression of the NF-κB/ROS–NLRP3 inflammasome axis. Male ApoE ^⁻/⁻ mice fed a high-fat diet for 8 weeks received vehicle, low-dose (3 mg/kg/day), or high-dose (10 mg/kg/day) resmetirom by oral gavage for an additional 8 weeks (n = 10/group). High-dose resmetirom reduced body weight gain by 50.8%, improved atherogenic dyslipidemia with approximate decreases of 35% in total cholesterol and 45% in LDL-cholesterol, and diminished aortic plaque burden as assessed by Oil Red O staining. Circulating inflammatory cytokines were markedly suppressed, with reductions in IL-1β (59%), IL-18 (62%), TNF-α (59%), and CRP (70%) compared with model controls. Western blot analysis revealed that aortic NLRP3, ASC, and caspase-1 protein levels decreased by 70–80%, findings corroborated by RT-qPCR and immunohistochemistry. Mechanistically, resmetirom reduced NF-κB p65 phosphorylation by approximately 50%, increased IκBα expression by 68%, and lowered aortic reactive oxygen species by 36%. Flow cytometry demonstrated that resmetirom repolarized lesional macrophages from a pro-inflammatory M1 toward an anti-inflammatory M2 phenotype, shifting the M1/M2 ratio from 2.28 to 0.62. These findings demonstrate that resmetirom exerts atheroprotective effects beyond lipid lowering by coordinately suppressing the NF-κB/ROS–NLRP3 inflammasome axis and reprogramming vascular macrophages, providing a mechanistic rationale for its therapeutic repurposing in atherosclerotic cardiovascular disease, particularly in patients with comorbid metabolic dysfunction.