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Understanding its molecular underpinnings to guide clinical management is crucial. Ferroptosis, a recently described non\u2010apoptotic form of cell death, is initiated by the lethal accumulation of iron\u2010dependent lipid peroxidation products. Despite growing interest, the roles and vulnerabilities determining ferroptosis sensitivity in BLCA remain unclear. Re\u2010analysis of single\u2010cell RNA data reveals a decrease in high\u2010ferroptosis cancer cells as BLCA advances. USP52\/PAN2 is identified as a key regulator of ferroptosis in BLCA through an unbiased siRNA screen targeting 96 deubiquitylases (DUBs). Functionally,\n                    <jats:italic>USP52<\/jats:italic>\n                    depletion impedes glutathione (GSH) synthesis by promoting xCT protein degradation, increasing lipid peroxidation and ferroptosis susceptibility, thus suppressing BLCA progression. Mechanistically, USP52 interacts with xCT and enzymatically cleaves the K48\u2010conjugated ubiquitin chains at K4 and K12, enhancing its protein stability. Clinical BLCA samples demonstrate a positive correlation between USP52 and xCT expression, with high USP52 levels associated with aggressive disease progression and poor prognosis. In vivo,\n                    <jats:italic>USP52<\/jats:italic>\n                    depletion combined with ferroptosis triggers imidazole ketone Erastin (IKE) synergistically restrains BLCA progression by inducing ferroptosis. These findings elucidate the role of the USP52\u2010xCT axis in BLCA and highlight the therapeutic potential of targeting USP52 and ferroptosis inducers in BLCA.\n                  <\/jats:p>","DOI":"10.1002\/advs.202403995","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T09:38:37Z","timestamp":1728639517000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Deubiquitylase USP52 Promotes Bladder Cancer Progression by Modulating Ferroptosis through Stabilizing SLC7A11\/xCT"],"prefix":"10.1002","volume":"11","author":[{"given":"Jianmin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Urology Zhongnan Hospital of Wuhan University  Wuhan 430071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongwen","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Urology Zhongnan Hospital of Wuhan University  Wuhan 430071 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