2. Academic Validation
  3. PHB2 ameliorates ferroptosis and aortic aneurysm/dissection through NEDD4L-dependent ubiquitination of NCOA4

PHB2 ameliorates ferroptosis and aortic aneurysm/dissection through NEDD4L-dependent ubiquitination of NCOA4

  • Redox Biol. 2026 May:92:104114. doi: 10.1016/j.redox.2026.104114.
Shengjun Xiong 1,  Jie Lin 1,  Ying An 1,  Yuxin Du 1,  Yiran E Li 1,  Zunhui Du 1,  Rongjun Zou 2,  Miyesaier Abudureyimu 3,  Junbo Ge 1,  Yingmei Zhang 4,  Jun Ren 5
Affiliations

Affiliations

  • 1 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China; National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China.
  • 2 Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510120, China.
  • 3 State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China; Cardiovascular Department, Shanghai Xuhui Central Hospital, Fudan University, Shanghai, 200031, China.
  • 4 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China; National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China. Electronic address: [email protected].
  • 5 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, China; National Health Commission (NHC) Key Laboratory of Ischemic Heart Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China. Electronic address: [email protected].
PMID: 41819783 DOI: 10.1016/j.redox.2026.104114
Abstract

Background: Aortic aneurysm/dissection (AAD) is a catastrophic vascular emergency with limited therapeutic options and poorly understood molecular underpinnings. Ferroptosis, an iron-dependent form of regulated cell death, emerged as a crucial driver of vascular degeneration although its pathological mechanisms in AAD remain largely undefined.

Methods: We integrated transcriptomic datasets to identify key dysregulated genes in AAD. PHB2 expression was examined by immunohistochemistry, immunofluorescence, and Western blotting in human tissues, murine models, and isolated vascular smooth muscle cells. Functional involvement of PHB2 was evaluated using VSMC-specific conditional knockout mice and AAV9-PHB2 overexpression in β-aminopropionitrile-evoked AAD model.

Results: Transcriptomic analysis revealed PHB2 as one of the most significantly downregulated genes in AAD, with selective suppression in VSMCs. Loss of PHB2 aggravated BAPN-induced aortic dilation, medial destruction, and elastic fiber fragmentation, whereas PHB2 overexpression preserved aortic wall integrity. RNAseq profiling implicated Ferroptosis as the dominant pathway activated by PHB2 deficiency. Functionally, PHB2 overexpression mitigated Ang II-induced lipid ROS accumulation and Fe2+ overload, while PHB2 silencing aggravated Ferroptosis. Mechanistically, rearranged subcellular localization of PHB2 promoted NCOA4 proteasomal degradation by interacting with NCOA4. PHB2 exhibited evident correlation with enhanced NEDD4L dimerization, enabling NEDD4L-mediated K48-linked ubiquitination of NCOA4 at Lys42, thus limiting ferritinophagy and suppressing Ferroptosis. In vivo, PHB2 deficiency decreased NCOA4 ubiquitination and promoted Ferroptosis, confirming the functional relevance of this pathway.

Conclusion: We identify a previously unrecognized PHB2-NEDD4L-NCOA4 regulatory axis that restrains Ferroptosis in VSMCs and protects against AAD progression. Targeting this pathway may represent a promising therapeutic strategy for the prevention and treatment of AAD.

Keywords

Aortic dissection; Ferroptosis; NCOA4; NEDD4L; PHB2; Ubiquitination.

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