DCAF7招募USP2以通过抑制生物钟自噬诱导的铁死亡促进肝细胞癌进展。
DCAF7 recruits USP2 to facilitate hepatocellular carcinoma progression by suppressing clockophagy-induced ferroptosis.
作者信息
Jiang Honglv, Wang Xiaohui, Zhu Zhenhua, Song Cheng, Li Dan, Yun Yixuan, Hui Li, Bao Leilei, O'Connor Darran P, Ma Jingjing, Xu Guoqiang
机构信息
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.
Research Center of Biological Psychiatry, Suzhou Guangji Hospital, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
出版信息
Cell Death Dis. 2025 Aug 28;16(1):654. doi: 10.1038/s41419-025-07977-3.
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.
DDB1和CUL4相关因子7（DCAF7）最近被确定为肿瘤发生的关键调节因子和铁死亡的潜在调节因子。然而，DCAF7在调节肝细胞癌（HCC）铁死亡进展中的精确功能仍不清楚。在本研究中，我们证明DCAF7和去泛素化酶USP2在HCC中高表达。DCAF7的基因敲除或USP2的药理学抑制使HCC对铁死亡敏感，并在体外和体内抑制HCC进展。机制上，DCAF7招募USP2以通过减少BMAL1 K63连接的多聚泛素化来抑制生物钟自噬（通过p62/SQSTM1介导的核心生物钟蛋白BMAL1的选择性自噬降解）。靶向DCAF7或USP2通过HIF1α-SLC7A11轴在HCC细胞中触发生物钟自噬诱导的铁死亡。总的来说，我们的研究将DCAF7和USP2确立为生物钟自噬诱导的铁死亡的新型抑制因子，并揭示了HCC治疗的潜在治疗靶点。
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