Plumbagin is a novel GPX4 protein degrader that induces apoptosis in hepatocellular carcinoma cells

Free Radic Biol Med. 2023 Jul:203:1-10. doi: 10.1016/j.freeradbiomed.2023.03.263. Epub 2023 Apr 1.


Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, remains a global health challenge requiring novel and effective therapeutic agents and approaches. Here, we found that a natural product plumbagin can inhibit the growth of HCC cells by inducing the downregulation of GPX4, but not other antioxidant enzymes such as CAT, SOD1, and TXN. Functionally, genetic silence of GPX4 enhances, whereas the overexpression of GPX4 inhibits plumbagin-induced apoptosis (rather than ferroptosis) in HCC cells. Furthermore, GPX4 protein specifically binds the deubiquitinase USP31, but not other deubiquitinases such as CYLD, USP1, USP14, USP20, USP30, USP38, UCHL1, UCHL3, and UCHL5. As an inhibitor of deubiquitinating enzymes, especially USP31, plumbagin induces ubiquitination of GPX4 and subsequent proteasomal degradation of GPX4 in HCC cells. Accordingly, plumbagin-mediated tumor suppression is also associated with the downregulation of GPX4 and the upregulation of apoptosis in a subcutaneous xenograft tumor model. Taken together, these findings demonstrate a novel anticancer mechanism of plumbagin by inducing GPX4 protein degradation.

Keywords: Deubiquitinase; GPX4; Hepatocellular carcinoma; Plumbagin; USP31; Ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Cell Line, Tumor
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Mitochondrial Proteins
  • Thiolester Hydrolases
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases / pharmacology


  • plumbagin
  • USP20 protein, human
  • Ubiquitin Thiolesterase
  • UCHL3 protein, human
  • USP14 protein, human
  • Usp30 protein, human
  • Thiolester Hydrolases
  • Mitochondrial Proteins
  • USP38 protein, human
  • Ubiquitin-Specific Proteases