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Randall's Plaques (RP) serve as a nidus for CaOx stones, but it remains poorly understood how renal interstitial hydroxyapatite (HAP) deposition erodes through the papillary urothelium to create sites for urinary CaOx crystal adherence. Here, it is observed loss of urothelium above interstitial HAP deposition, and revealed that Fas Ligand (FASLG) derived from renal interstitial fibroblasts (RIFs) in HAP\u2010rich microenvironment induced anoikis of urothelium to trigger RP exposure to urine. Mechanistically, HAP interacted with membrane protein THY1 of RIFs, which increased the affinity of THY1 to SFRP1 but suppressed its affinity to NDP, leading to activation of GSK3\u03b1\/\u03b2\u2013\u03b2\u2010catenin pathway and thus upregulating FASLG. Moreover, the upregulated FASLG is identified as the predictor for recurrence in patients with CaOx stones following lithotripsy. Furthermore, Benarthin, a small compound binding to THY1, is found to inhibit HAP\u2010induced FASLG and thus attenuate the anoikis of urothelium in RP mice. It is anticipated that investigations of urothelial anoikis caused by FASLG from HAP\u2010induced fibroblasts will offer novel insights into RP exposure, enabling preventive strategies for CaOx stone formation.<\/jats:p>","DOI":"10.1002\/advs.202521605","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T18:55:43Z","timestamp":1775156143000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["FASLG Derived from Fibroblasts in Hydroxyapatite\u2010Rich Microenvironment Induces Urothelial Anoikis to Trigger Randall's Plaque Exposure"],"prefix":"10.1002","volume":"13","author":[{"given":"Minghui","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Urology Xiangya Hospital Central South University  Changsha Hunan China"},{"name":"National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University  Changsha Hunan 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