2. Academic Validation
  3. Endothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the miR-32-5p/neurofibromin 2 pathway

Endothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the miR-32-5p/neurofibromin 2 pathway

  • Eur J Med Res. 2025 Jun 6;30(1):463. doi: 10.1186/s40001-025-02716-y.
Ying Deng # 1 2,  Xueguang Lin # 1 3,  Jun Wei # 4,  Bo Chen # 1 3,  Huafang Yan 5,  Bo Wang 1 3,  Jialong Li 1 3,  Yuqun Zhao 6,  Bo Yu 1 3 7,  Jingdong Tang 1 3,  Shuai Jiang 8 9
Affiliations

Affiliations

  • 1 Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, Shanghai, 201399, China.
  • 2 Fudan Zhangjiang Institute, Shanghai, China.
  • 3 Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China.
  • 4 Southern Medical University Affiliated Fengxian Hospital, Shanghai, China.
  • 5 Physical Examination Center, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
  • 6 Shan Xi Yi Kang Vasculitis Hospital, Taiyuan, Shanxi, China.
  • 7 Department of Vascular Surgery, Huashan Hospital, Fudan University, Shanghai, China.
  • 8 Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, Shanghai, 201399, China. zhiyusang@163.com.
  • 9 Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China. zhiyusang@163.com.
  • # Contributed equally.
PMID: 40481609 DOI: 10.1186/s40001-025-02716-y
Abstract

Thromboangiitis obliterans (TAO) is characterized by progressive inflammatory vasculopathy featuring thrombotic occlusion. Aberrant thrombosis induces endothelial damage through pathological clotting, while iron may act as a pro-oxidant cofactor. However, the function and mechanism of iron in TAO pathogenesis and endothelial damage remain to be elucidated. In the current study, the iron status and key lipid peroxidation markers (MDA, 4HNE, and ACSL4) were evaluated in patients with TAO and the sodium laurate-induced rat model. The CCK-8 assay, immunofluorescence, western blot, qPCR, and transmission electron microscopy were employed to detect iron overload and Ferroptosis in vascular endothelial cells. In addition, bioinformatics analysis, luciferase reporter gene assay, qPCR, and western blot were used to confirm the miR-32-5p/Neurofibromin-2 (NF2) pathway in vitro. The therapeutic feasibility was validated by deferoxamine and Ferrostatin-1 treatment in vivo. The results showed iron overload and increased TFR1 expression in the vessel lesions of patients with TAO, as well as significant increases in MDA, 4HNE, and ACSL4. Serum from patients with TAO increased intracellular iron and lipid peroxidation and decreased the viability of HUVECs in vitro. Mechanism studies indicated that exosomal miR-32-5p increased in patients with TAO and could target and decrease the expression of NF2, which then decreased the phosphorylation of YAP at Ser109 and Ser217 sites. Then the NF2-targeted genes TFR1 and ACSL4 were upregulated. Finally, deferoxamine and Ferrostatin-1 treatment relieved the disease score, inflammation, and Ferroptosis in vivo. This study newly demonstrates that iron overload and Ferroptosis are key risk factors in patients with TAO and that the exosomal miR-32-5p/NF2 pathway may play an important role in TAO pathogenesis.

Keywords

Ferroptosis; Iron metabolism; Neurofibromin 2; Thromboangiitis obliterans.

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