2. Academic Validation
  3. DCAF7 recruits USP2 to facilitate hepatocellular carcinoma progression by suppressing clockophagy-induced ferroptosis

DCAF7 recruits USP2 to facilitate hepatocellular carcinoma progression by suppressing clockophagy-induced ferroptosis

  • Cell Death Dis. 2025 Aug 28;16(1):654. doi: 10.1038/s41419-025-07977-3.
Honglv Jiang 1,  Xiaohui Wang 1,  Zhenhua Zhu 2,  Cheng Song 1,  Dan Li 1,  Yixuan Yun 1,  Li Hui 2,  Leilei Bao 3,  Darran P O'Connor 4,  Jingjing Ma 5,  Guoqiang Xu 6 7 8 9
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases and College of Pharmaceutical Sciences, The Fourth Affiliated Hospital of Soochow University, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu, China.
  • 2 Research Center of Biological Psychiatry, Suzhou Guangji Hospital, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
  • 3 Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
  • 4 Department of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
  • 5 Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, Jiangsu, China. jingjingmajj@suda.edu.cn.
  • 6 Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases and College of Pharmaceutical Sciences, The Fourth Affiliated Hospital of Soochow University, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu, China. gux2002@suda.edu.cn.
  • 7 Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China. gux2002@suda.edu.cn.
  • 8 MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China. gux2002@suda.edu.cn.
  • 9 Suzhou Key Laboratory of Geriatric Neurological Disorders, the First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. gux2002@suda.edu.cn.
PMID: 40877242 DOI: 10.1038/s41419-025-07977-3
Abstract

DDB1- and CUL4-associated factor 7 (DCAF7) has recently been identified as a critical regulator of tumorigenesis and a potential modulator of Ferroptosis. However, the precise function of DCAF7 in regulating the progression of hepatocellular carcinoma (HCC) Ferroptosis remains elusive. In this study, we demonstrate that DCAF7 and the Deubiquitinase USP2 are highly expressed in HCC. Genetic ablation of DCAF7 or pharmacological inhibition of USP2 sensitizes HCC to Ferroptosis and inhibits HCC progression both in vitro and in vivo. Mechanistically, DCAF7 recruits USP2 to inhibit clockophagy (the selective autophagic degradation of core clock protein BMAL1 mediated through p62/SQSTM1) by reducing BMAL1 K63-linked polyubiquitination. Targeting either DCAF7 or USP2 triggers clockophagy-induced Ferroptosis through the HIF1α-SLC7A11 axis in HCC cells. Collectively, our study establishes DCAF7 and USP2 as novel suppressors of clockophagy-induced Ferroptosis and reveals the potential therapeutic targets for HCC treatment.

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