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Here, we identified tumor necrosis factor\u2010\u03b1 (TNF\u03b1) as a key inducer of mitochondrial dysfunction and EndMT in endothelial cells of renal allografts. Importantly, TNF\u03b1 simultaneously activated BNIP3\u2010dependent mitophagy as a compensatory response, which removed damaged mitochondria, restrained EndMT, and attenuated renal allograft interstitial fibrosis. In addition, inhibition of BNIP3 promoted the accumulation of damaged mitochondria, aggravated EndMT, and exacerbated renal allograft interstitial fibrosis, supporting a protective role of mitophagy. Mechanistically, TNF\u03b1 upregulated and stabilized HIF\u20101\u03b1 by disrupting its NEDD4\u2010mediated ubiquitination, thereby enhancing BNIP3 transcription to drive mitophagy. Moreover, endothelial\u2010specific deletion of HIF\u20101\u03b1 impaired this compensatory pathway, aggravated mitochondrial dysfunction, and exacerbated renal allograft interstitial fibrosis. Thus, compensatory mitophagy through the NEDD4\/HIF\u20101\u03b1\/BNIP3 pathway represented a potential protective stress\u2010adaptation program in renal allograft endothelial cells, providing mechanistic insight and a conceptual framework for future therapeutic exploration aimed at preserving renal allograft function.<\/jats:p>","DOI":"10.1002\/advs.202516953","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T03:31:42Z","timestamp":1789961502000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Compensatory Mitophagy via NEDD4\/HIF\u20101\u03b1\/BNIP3 Pathway Restrains EndMT and Renal Allograft Interstitial Fibrosis Induced by TNF\u03b1"],"prefix":"10.1002","volume":"13","author":[{"given":"Dengyuan","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Urology the First Affiliated Hospital with Nanjing Medical University Nanjing China"},{"name":"Department 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