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This study demonstrates that XPC deficiency in bladder cancer cells can promote autophagy in response to the cisplatin\u2010mediated DNA damage response (DDR). This process is closely related to both the overexpression of KDM4A and the downregulation of PHRF1 induced by the overactivation of ATM phosphate. The overaccumulation of KDM4A can suppress PHRF1 expression and result in significant nuclear accumulation of the p53 protein. Notably, this study defines a new mechanism by which PHRF1 regulates p53 posttranslationally through the ubiquitin\u2010proteasome system. In XPC low expression cells, PHRF1 performs a more critical E3 ubiquitin ligase function than MDM2. Especially under conditions of cisplatin\u2010mediated DNA damage where MDM2 function is impaired, PHRF1 retains its functionality. In a mouse xenograft model, combining a KDM4 inhibitor with cisplatin results in superior antitumor effects compared with cisplatin alone. These findings provide new insights into the phenotypic plasticity of bladder cancer under drug resistance and highlight the potential of KDM4A inhibition and preservation of PHRF1 function in overcoming cisplatin resistance. Therefore, KDM4A or PHRF1 may be potential novel targets for the treatment of bladder cancer.<\/jats:p>","DOI":"10.1002\/advs.202517563","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T08:49:07Z","timestamp":1762850947000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["XPC Deficiency Activate Cisplatin\u2010Mediated Autophagy in Bladder Cancer by Limiting Novel PHRF1\u2010Mediated Ubiquitination of the p53 Protein"],"prefix":"10.1002","volume":"13","author":[{"given":"Baixiong","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Urology The First Affiliated Hospital (Southwest Hospital) of Army Medical University  Chongqing 400038 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology Army Medical University  Chongqing 400038 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