FASLG Derived from Fibroblasts in Hydroxyapatite‐Rich Microenvironment Induces Urothelial Anoikis to Trigger Randall's Plaque Exposure

ABSTRACT Calcium Oxalate (CaOx) kidney stones with high recurrence are a major clinical and economic health burden. 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‐rich 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 GSK3α/β–β‐catenin 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‐induced FASLG and thus attenuate the anoikis of urothelium in RP mice. It is anticipated that investigations of urothelial anoikis caused by FASLG from HAP‐induced fibroblasts will offer novel insights into RP exposure, enabling preventive strategies for CaOx stone formation.