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Transient receptor potential melastatin-8 (TRPM8) is a calcium-permeable channel known for its involvement in neuropathic pain and respiratory disorders; however, its potential impact on cardiovascular health, particularly in hyperlipidemia and atherosclerosis, remains a compelling mystery. In this study, we aimed to investigate the role and mechanisms of TRPM8 in the development of atherosclerosis. The apolipoprotein E deficient (apoe-/-) mice and apoe-/-trpm8-/- mice were used in our in vivo model. Genetic ablation of TRPM8 in apoe-/- mice exacerbated aortic inflammation and atherosclerosis. Moreover, the lipid profiles in the liver of apoe-/-trpm8-/- mice showed significant elevations across the board, including total cholesterol, free cholesterol, cholesterol esters, triglycerides, fatty acids, and glycerol. LC-MS/MS analysis further uncovered that TRPM8 deficiency in the liver of apoe-/- mice led to a cascade of metabolic disruptions: mitochondrial dysfunction impaired fatty acid -oxidation and reduced ATP production, excess acetyl-CoA was channeled into lipid synthesis, resulting in hepatic lipid accumulation. Moreover, genetic deletion of TRPM8 in the liver of apoe-/- mice impaired cellular quality control mechanisms, evidenced by compromised autophagy flux and decreased proteasomal activity. This disruption of proteostasis, marked by increased protein ubiquitination and coupled with lipid accumulation-induced oxidative stress, culminated in liver cell damage and apoptosis. These results underscore the biological role of TRPM8 in regulating lipid metabolism, mitigating hyperlipidemia, and potentially protecting against the development of atherosclerosis.