2. Academic Validation
  3. USP24 promotes autophagy-dependent ferroptosis in hepatocellular carcinoma by reducing the K48-linked ubiquitination of Beclin1

USP24 promotes autophagy-dependent ferroptosis in hepatocellular carcinoma by reducing the K48-linked ubiquitination of Beclin1

  • Commun Biol. 2024 Oct 8;7(1):1279. doi: 10.1038/s42003-024-06999-5.
Jiahui Cao # 1,  Shitao Wu # 1,  Senfeng Zhao # 1,  Libo Wang 1,  Yahui Wu 1,  Liming Song 1,  Chenguang Sun 1,  Yin Liu 1,  Zhipu Liu 1,  Rongtao Zhu 1 2 3,  Ruopeng Liang 1 2 3,  Weijie Wang 1 2 3,  Yuling Sun 4 5 6
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • 2 Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, 450052, China.
  • 3 Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, 450052, China.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. ylsun@zzu.edu.cn.
  • 5 Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, 450052, China. ylsun@zzu.edu.cn.
  • 6 Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, 450052, China. ylsun@zzu.edu.cn.
  • # Contributed equally.
PMID: 39379617 DOI: 10.1038/s42003-024-06999-5
Abstract

Ubiquitination is a post-translational modification (PTM), which is critical to maintain cell homeostasis. Ubiquitin-Specific Protease 24 (USP24) plays roles in various diseases, the mechanisms by which USP24 regulates hepatocellular carcinoma (HCC) remain poorly understood. In this study, USP24 is found to be significantly downregulated in HCC. Knocking down USP24 promotes HCC proliferation and migration, whereas USP24 overexpression inhibits HCC in vitro and in vivo. The endogenous interaction between USP24 and Beclin1 is confirmed. Mechanically, USP24 delays Beclin1 degradation by reducing its K48-linked ubiquitination, the effects of overexpressing USP24 on HCC proliferation can be partially reversed by silencing Beclin1. We find that increased Autophagy is accompanied by Ferroptosis in USP24 overexpressed HCC cells and USP24 increases the susceptibility of HCC to sorafenib. Collectively, this study highlights the critical role of USP24 in regulating autophagy-dependent Ferroptosis by decreasing Beclin1 ubiquitination, suggesting that targeting USP24 may be a strategy for treating HCC.

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