2. Academic Validation
  3. Chronic intermittent cold stress-induced lipophagy promotes foamy macrophage susceptibility to ferroptosis and exacerbates atherosclerosis

Chronic intermittent cold stress-induced lipophagy promotes foamy macrophage susceptibility to ferroptosis and exacerbates atherosclerosis

  • Free Radic Biol Med. 2026 Jan:242:636-653. doi: 10.1016/j.freeradbiomed.2025.11.010.
Yajie Zhao 1,  Qianbing Wang 1,  Tielie Gao 2,  Xue Guan 1,  Tianwei Guo 1,  Tianzuo Chen 3,  Yan Yang 1,  Pengbo Sun 1,  Mi Yang 1,  Xing Luo 4,  Liming Yang 5,  Hong Li 6,  Jiayuan Kou 7
Affiliations

Affiliations

  • 1 Department of Pathophysiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, 150000, China.
  • 2 Department of Forensic Medicine, Harbin Medical University, Harbin, 150081, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, 150000, China.
  • 4 Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China.
  • 5 Department of Pathophysiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, 150000, China; Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. Electronic address: [email protected].
  • 6 Department of Pathophysiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
  • 7 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
PMID: 41205774 DOI: 10.1016/j.freeradbiomed.2025.11.010
Abstract

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. Single-cell RNA Sequencing, immunofluorescence and electron microscopy analyses confirmed that cold stress induced Ferroptosis in foamy macrophages, accompanied by iron overload and lipid peroxidation, and upregulated ALOX15 while downregulating GPX4. Mechanistically, cold stress promoted corticosterone (CORT) release, which activated the Glucocorticoid Receptor (GR) to induce excessive lipophagy, enhancing ALOX15-mediated polyunsaturated fatty acid (PUFA) peroxidation. Simultaneously, cold stress impaired the interaction between p62 and KEAP1, indirectly suppressing NRF2-mediated GPX4 expression, synergistically inducing Ferroptosis. In vitro studies further revealed that p62 overexpression or KEAP1 knockdown significantly restored total NRF2 protein levels and reversed the inhibition of its nuclear translocation. Conversely, NRF2 overexpression and GR antagonists effectively reversed the downregulation of GPX4, the elevation of MDA levels, and the accumulation of Fe2+. In vivo, metyrapone (CORT inhibitor) and Ferrostatin-1 (Ferroptosis inhibitor) effectively attenuated Ferroptosis in foamy macrophages and AS progression. Therefore, targeting Ferroptosis or CORT signaling may represent novel therapeutic strategies for AS.

Keywords

Atherosclerosis; CORT; Chronic intermittent cold stress; Ferroptosis; Lipophagy.

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