REGγ Suppresses Ferroptosis and Induces Drug Resistance by Degrading WDR6 in Chondrosarcoma

Chondrosarcoma (CS) is a malignant bone tumor for which treatment efficacy remains clinically challenging owing to chemotherapy resistance. Ferroptosis, an iron-dependent 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 REGγ as a critical driver of malignant progression in chondrosarcoma, with its elevated expression correlating with unfavorable patient outcomes. Loss of REGγ potentiates lipid peroxidation and modulates the activation of ferroptosis-associated genes by enhancing WDR6 protein stability. Mechanistically, REGγ degrades WDR6 through a ubiquitin-independent mechanism, inhibiting the ferroptosis pathway governed by the STK11/AMPK axis and consequently promoting tumor drug resistance. Additionally, RLY01, an inhibitor of the REGγ-20S proteasome, effectively suppresses chondrosarcoma growth and sensitizes chondrosarcoma cells to cisplatin. Collectively, REGγ emerges as a highly promising therapeutic target for improving the efficacy of cisplatin and other chemotherapies in CS.