REGγ Suppresses Ferroptosis and Induces Drug Resistance by Degrading WDR6 in Chondrosarcoma
Fanrong Liu, Shihui Shen, Dongxia Li, Peilin Shi, Jiaming Xu, Tongxin Lv, Yingying Du, Jingwei Zhang, Bo Yang, Hansen Chen, Zhuoya Peng, Wenjie Ren, Lu Zhang, Sheng Cheng, Tongjin Yin, Wencai Sheng, Lei Li, Juan Wu, Qingcheng Yang, Shuogui Xu, Wei ZhengABSTRACT
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.