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

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.