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To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl\u2010XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib\u2010induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl\u2010XL. The intervention effect is dependent on the alleviation of the nilotinib\u2010induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin\u2012proteasome degradation of Bcl\u2010XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl\u2010XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity.<\/jats:p>","DOI":"10.1002\/advs.202302002","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T23:16:45Z","timestamp":1689376605000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Chloroquine Intervenes Nephrotoxicity of Nilotinib through Deubiquitinase USP13\u2010Mediated Stabilization of Bcl\u2010XL"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0578-7212","authenticated-orcid":false,"given":"Hao","family":"Yan","sequence":"first","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University College of Pharmaceutical Sciences Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5896-6885","authenticated-orcid":false,"given":"Xiangliang","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University College of Pharmaceutical Sciences Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1896-097X","authenticated-orcid":false,"given":"Jiangxin","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University College of Pharmaceutical Sciences Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University College of Pharmaceutical Sciences Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University College of Pharmaceutical Sciences Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifei","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University College of Pharmaceutical Sciences Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University College of Pharmaceutical Sciences Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Zhejiang Cancer Hospital  Hangzhou 310005 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2248-5235","authenticated-orcid":false,"given":"Xiaochun","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University College of Pharmaceutical Sciences Zhejiang University  Hangzhou 310058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-2771","authenticated-orcid":false,"given":"Bo","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology &amp; 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