2. Academic Validation
  3. ANXA1 inhibits ferroptosis in HUVECs via negative regulation of ferritinophagy

ANXA1 inhibits ferroptosis in HUVECs via negative regulation of ferritinophagy

  • Exp Cell Res. 2026 Jan 1;454(1):114825. doi: 10.1016/j.yexcr.2025.114825.
Jingjing Wang 1,  Jinqiu Jia 1,  Zitong Cao 1,  Zeming Cai 2,  Kai Zhang 3,  Jin He 4,  Chunyan Wu 5,  Zuo Wang 6
Affiliations

Affiliations

  • 1 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 2 Department of Pediatrics, The First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, China.
  • 3 Department of Intensive Care Unit, The Second Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, China.
  • 4 Functional Department, The First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, China.
  • 5 Cardiology Department, The Third Affiliated Hospital of University of South China, Hengyang, Hunan, 421900, China. Electronic address: [email protected].
  • 6 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
PMID: 41241173 DOI: 10.1016/j.yexcr.2025.114825
Abstract

Ferroptosis is a phospholipid peroxidation-mediated and iron-dependent cell death form. Inhibiting Ferroptosis is a promising strategy for the prevention and treatment of cardiovascular diseases. Annexin A1 (ANXA1) is an endogenous anti-inflammatory mediator that plays an important regulatory role in cardiovascular diseases such as atherosclerosis, especially in inflammation suppression, protecting the heart from injury, and regulating vascular function. Ac2-26 is a synthetic peptide derived from the N-terminal 26 Amino acids of ANXA1, which retains its anti-inflammatory properties. However, the regulatory mechanism of ANXA1 in atherosclerosis (AS) is not yet fully understood. This study aims to explore the specific role of Ferroptosis in HUVECs and demonstrate that ANXA1 can disrupt ferritinophagy and protect endothelial function. Treatment with Ac2-26 or ANXA1-overexpressing HUVECs alleviated RSL3-induced endothelial cell dysfunction and inhibited lipid peroxidation, as evidenced by a reduction in ferrous ion levels and upregulation of GPX4, FTH1, and SLC7A11 protein expression, along with a downregulation of LC3-II and NCOA4 expression. In contrast, knockdown of ANXA1 in HUVECs failed to suppress the outcome of Ferroptosis. Furthermore, co-immunoprecipitation analysis revealed that ANXA1 overexpression prevented ferritin degradation by disrupting the NCOA4-FTH1 protein-protein interaction, reducing the bioavailability of intracellular ferrous ions, thereby blocking Ferroptosis. In conclusion, our findings identify a novel mechanism, showing that ANXA1 can inhibit Ferroptosis via ferritinophagy, thereby alleviating endothelial dysfunction, which may provide a new therapeutic avenue for AS.

Keywords

ANXA1,FTH1,NCOA4,Ferroptosis; Ferritinophagy.

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