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journal article·2026-06-26Open access

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 Zheng

Advanced Science
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Abstract

ABSTRACT 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.
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Research context

OpenAlex topics: Ferroptosis and cancer prognosis · Cancer, Lipids, and Metabolism · Cancer-related molecular mechanisms research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Orthopedics Shanghai Sixth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine Shanghai China

College of Medicine Southwest JiaoTong University Chengdu China

East China Normal University‐Shanghai Putuo District Central Hospital Collaborative Research Center For Translational Medicine Shanghai Putuo District Central Hospital Shanghai China

Zhejiang University‐University of Edinburgh Institute (ZJU‐UoE Institute) Zhejiang University Haining Zhejiang China

Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences School of Life Sciences East China Normal University Shanghai China

College of Metrology Measurement and Instrument China Jiliang University Hangzhou Zhejiang China

Department of Emergency and Trauma the First Affiliated Hospital of Naval Medical University Shanghai China

Department of Pediatrics Affiliated Hospital 6 of Nantong University Pediatrics Department of Yancheng Third People's Hospital Yancheng China

Department of Pharmacy The General Hospital of Western Theater Command Chengdu Chengdu China

Funding

National Natural Science Foundation of China · Shanghai Municipal Education Commission

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