Endothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the miR-32-5p/neurofibromin 2 pathway
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...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-06-01
|
| Series: | European Journal of Medical Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40001-025-02716-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850137811634618368 |
|---|---|
| author | Ying Deng Xueguang Lin Jun Wei Bo Chen Huafang Yan Bo Wang Jialong Li Yuqun Zhao Bo Yu Jingdong Tang Shuai Jiang |
| author_facet | Ying Deng Xueguang Lin Jun Wei Bo Chen Huafang Yan Bo Wang Jialong Li Yuqun Zhao Bo Yu Jingdong Tang Shuai Jiang |
| author_sort | Ying Deng |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b76ce5ce54204946a2860f2ca99d7874 |
| institution | OA Journals |
| issn | 2047-783X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | European Journal of Medical Research |
| spelling | doaj-art-b76ce5ce54204946a2860f2ca99d78742025-08-20T02:30:45ZengBMCEuropean Journal of Medical Research2047-783X2025-06-0130111310.1186/s40001-025-02716-yEndothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the miR-32-5p/neurofibromin 2 pathwayYing Deng0Xueguang Lin1Jun Wei2Bo Chen3Huafang Yan4Bo Wang5Jialong Li6Yuqun Zhao7Bo Yu8Jingdong Tang9Shuai Jiang10Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Key Laboratory of Vascular Lesions Regulation and RemodelingDepartment of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Key Laboratory of Vascular Lesions Regulation and RemodelingSouthern Medical University Affiliated Fengxian HospitalDepartment of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Key Laboratory of Vascular Lesions Regulation and RemodelingPhysical Examination Center, Shanghai Pudong Hospital, Fudan University Pudong Medical CenterDepartment of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Key Laboratory of Vascular Lesions Regulation and RemodelingDepartment of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Key Laboratory of Vascular Lesions Regulation and RemodelingShan Xi Yi Kang Vasculitis HospitalDepartment of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Key Laboratory of Vascular Lesions Regulation and RemodelingDepartment of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Key Laboratory of Vascular Lesions Regulation and RemodelingDepartment of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Key Laboratory of Vascular Lesions Regulation and RemodelingAbstract 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.https://doi.org/10.1186/s40001-025-02716-yThromboangiitis obliteransFerroptosisIron metabolismNeurofibromin 2 |
| spellingShingle | Ying Deng Xueguang Lin Jun Wei Bo Chen Huafang Yan Bo Wang Jialong Li Yuqun Zhao Bo Yu Jingdong Tang Shuai Jiang Endothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the miR-32-5p/neurofibromin 2 pathway European Journal of Medical Research Thromboangiitis obliterans Ferroptosis Iron metabolism Neurofibromin 2 |
| title | Endothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the miR-32-5p/neurofibromin 2 pathway |
| title_full | Endothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the miR-32-5p/neurofibromin 2 pathway |
| title_fullStr | Endothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the miR-32-5p/neurofibromin 2 pathway |
| title_full_unstemmed | Endothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the miR-32-5p/neurofibromin 2 pathway |
| title_short | Endothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the miR-32-5p/neurofibromin 2 pathway |
| title_sort | endothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the mir 32 5p neurofibromin 2 pathway |
| topic | Thromboangiitis obliterans Ferroptosis Iron metabolism Neurofibromin 2 |
| url | https://doi.org/10.1186/s40001-025-02716-y |
| work_keys_str_mv | AT yingdeng endothelialcellironoverloadandferroptosismediatethrombosisandinflammationthroughthemir325pneurofibromin2pathway AT xueguanglin endothelialcellironoverloadandferroptosismediatethrombosisandinflammationthroughthemir325pneurofibromin2pathway AT junwei endothelialcellironoverloadandferroptosismediatethrombosisandinflammationthroughthemir325pneurofibromin2pathway AT bochen endothelialcellironoverloadandferroptosismediatethrombosisandinflammationthroughthemir325pneurofibromin2pathway AT huafangyan endothelialcellironoverloadandferroptosismediatethrombosisandinflammationthroughthemir325pneurofibromin2pathway AT bowang endothelialcellironoverloadandferroptosismediatethrombosisandinflammationthroughthemir325pneurofibromin2pathway AT jialongli endothelialcellironoverloadandferroptosismediatethrombosisandinflammationthroughthemir325pneurofibromin2pathway AT yuqunzhao endothelialcellironoverloadandferroptosismediatethrombosisandinflammationthroughthemir325pneurofibromin2pathway AT boyu endothelialcellironoverloadandferroptosismediatethrombosisandinflammationthroughthemir325pneurofibromin2pathway AT jingdongtang endothelialcellironoverloadandferroptosismediatethrombosisandinflammationthroughthemir325pneurofibromin2pathway AT shuaijiang endothelialcellironoverloadandferroptosismediatethrombosisandinflammationthroughthemir325pneurofibromin2pathway |