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Ferroptosis, an iron\u2010dependent form of regulated cell death initiated by lipid peroxidation, has emerged as a promising strategy for addressing drug resistance. However, the potential of targeting ferroptosis to overcome drug resistance in CS has not been systematically elucidated. Our study identifies REG\u03b3 as a critical driver of malignant progression in chondrosarcoma, with its elevated expression correlating with unfavorable patient outcomes. Loss of REG\u03b3 potentiates lipid peroxidation and modulates the activation of ferroptosis\u2010associated genes by enhancing WDR6 protein stability. Mechanistically, REG\u03b3 degrades WDR6 through a ubiquitin\u2010independent mechanism, inhibiting the ferroptosis pathway governed by the STK11\/AMPK axis and consequently promoting tumor drug resistance. Additionally, RLY01, an inhibitor of the REG\u03b3\u201020S proteasome, effectively suppresses chondrosarcoma growth and sensitizes chondrosarcoma cells to cisplatin. Collectively, REG\u03b3 emerges as a highly promising therapeutic target for improving the efficacy of cisplatin and other chemotherapies in CS.<\/jats:p>","DOI":"10.1002\/advs.76293","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T12:46:41Z","timestamp":1782478001000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["REG\u03b3 Suppresses Ferroptosis and Induces Drug Resistance by Degrading WDR6 in Chondrosarcoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Fanrong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Orthopedics Shanghai Sixth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine Shanghai China"},{"name":"College of Medicine Southwest JiaoTong University Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihui","family":"Shen","sequence":"additional","affiliation":[{"name":"East 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