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Endoplasmic reticulum stress (ER stress) often occurs in the kidneys during AKI, regulating protein translation and post\u2010translational modification. E\u2010cadherin, a key regulator of cell polarity, undergoes O\u2010glycosylated during ER stress. However, the role of E\u2010cadherin O\u2010glycosylation in kidney injury and repair remains to be elucidated. Cisplatin (CP)\/lipopolysaccharide (LPS)\u2010induced AKI mouse models and cell models were established to evaluate ER stress in the RTECs. The glycan modification and localization of E\u2010cadherin, as well as its interaction with \u03b2\u2010catenin, were evaluated in vitro through Western blot, immunoprecipitation, and immunofluorescence. Small molecular inhibitors targeting ER stress (4\u2010PBA) or O\u2010glycosylation (OSMI\u20101) were utilized to investigate the effects on E\u2010cadherin O\u2010glycosylation, RTECs polarity and proliferation in vivo and in vitro. Both CP\u2010 and LPS\u2010induced AKI triggered ER stress in RTECs, which led to O\u2011glycosylation of E\u2011cadherin, loss of cell polarity, and impaired proliferation. Notably, removal of a brief ER stress pulse allowed RTECs to regain normal polarity and proliferation, indicating the reversibility of this process. Consistently, pharmacological inhibition of ER stress or O\u2011glycosylation effectively restored these phenotypes in vitro. Moreover, in vivo suppression of ER stress in CP\u2011induced AKI mice significantly recovered renal function and promoted tubular cell proliferation. Together, these results establish ER stress\u2011driven E\u2011cadherin O\u2011glycosylation as a critical upstream event in AKI\u2011associated tubular repair failure and suggest that targeting this axis holds therapeutic promise. These findings establish ER stress\u2010driven E\u2010cadherin O\u2010glycosylation as a critical upstream mechanism of tubular repair failure in AKI, and suggest that targeting this axis represents a promising therapeutic strategy for restoring renal function.<\/jats:p>","DOI":"10.1002\/jbt.71061","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T10:41:59Z","timestamp":1786358519000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["O\u2010Glycosylation of E\u2010Cadherin Induced by Endoplasmic Reticulum Stress Negatively Regulates Cell Polarity and Proliferation in Acute Kidney Injury"],"prefix":"10.1002","volume":"40","author":[{"given":"Yingjia","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Nephrology, Zhongshan Hospital Fudan University Shanghai 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