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We previously reported that protein tyrosine phosphatase nonreceptor type 14 (PTPN14) is implicated in atherosclerosis. Its role in flow\u2010dependent endothelial dysfunction and the upstream regulatory mechanisms remain incompletely understood. Here, we show that PTPN14 functions as a flow\u2010sensitive regulator in endothelial cells, with its protein stability reduced under disturbed flow. Endothelial\u2010specific deletion of PTPN14 led to exacerbated endothelial inflammation and atherosclerosis in vivo. We further identify TRIM21 as a critical E3 ubiquitin ligase that binds PTPN14 via its SPRY domain and promotes K48\u2010linked polyubiquitination at lysine 956, resulting in proteasomal degradation of PTPN14. Notably, disturbed flow induced TRIM21 LLPS in a cytoskeleton\u2010dependent manner, facilitating the recruitment of PTPN14 into co\u2010condensates and enhancing its ubiquitination. Endothelial\u2010specific TRIM21 overexpression aggravated disturbed flow\u2010induced endothelial inflammation and atherosclerosis. In contrast, endothelial\u2010specific TRIM21 deficiency attenuated induced endothelial activation and atherosclerosis; importantly, this atheroprotective effect was abolished by concomitant PTPN14 deletion, establishing a functional TRIM21\u2010PTPN14 regulatory axis in vivo. Together, these findings uncover phase separation\u2010dependent ubiquitin signaling as a mechanistic link between hemodynamic forces and endothelial dysfunction and suggest the TRIM21\u2010PTPN14 pathway as a potential therapeutic target in atherosclerosis.<\/jats:p>","DOI":"10.1002\/advs.77262","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:54:49Z","timestamp":1787050489000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phase Separation of TRIM21 Modulates PTPN14 Stability to Drive Flow\u2010Dependent Endothelial Activation and Atherogenesis"],"prefix":"10.1002","author":[{"given":"Xue","family":"He","sequence":"first","affiliation":[{"name":"Province and Ministry Co\u2010Sponsored Collaborative Innovation Center for Medical Epigenetics Eye Institute and School of Optometry Tianjin Medical University Eye Hospital Tianjin Medical University  Tianjin China"},{"name":"NHC 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