Chronic Intermittent Cold Stress-induced lipophagy promotes foamy macrophage susceptibility to ferroptosis and exacerbates atherosclerosis

Chronic intermittent cold stress significantly exacerbates the progression of atherosclerosis (AS), but the underlying mechanisms remain unclear. Emerging evidence suggests that ferroptosis in foamy macrophages contributes to plaque instability. This study aimed to investigate whether cold stress promotes AS by inducing ferroptosis in foamy macrophages and to explore the molecular pathways involved. The results demonstrated that Cold stress accelerated AS progression in HFD-fed ApoE-/- mice, characterized by increased plaque thickness, necrotic core expansion, collagen reduction, and aggravated inflammation. Aortic single-cell RNA sequencing, immunofluorescence and electron microscopy analysis confirmed cold stress induced ferroptosis in foamy macrophages, accompanied by iron overload and lipid peroxidation, and downregulated GPX4.