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

作者：Shengjun Xiong, Jie Lin, Ying An, Yuxin Du, Yiran E. Li, Zunhui Du, Rongjun Zou, Miyesaier Abudureyimu, Junbo Ge, Yingmei Zhang, Jun Ren · 发表于：Redox Biology · 年份：2026 · DOI：10.1016/j.redox.2026.104114 · 被引用次数：2 · 研究领域：Ferroptosis and cancer prognosis、Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways

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. 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 (VSMCs). Functional involvement of PHB2 was evaluated using VSMC-specific conditional knockout mice (Tagln-Cre; PHB2 flox/flox ) and AAV9-PHB2 overexpression in β-aminopropionitrile (BAPN)-evoked AAD model. 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 Fe 2+ overload, while PHB2 silencing aggravated ferroptosis. Mechanistically, rearranged subcellular localization of PHB2 promoted NCOA4 proteasomal degradation by interacting with NCOA4. PHB2 exhibited evident correlation w...