Targeting USP18 overcomes acquired resistance in hepatocellular carcinoma by regulating NCOA4 deISGylation and ferroptosis

• Published in: Cell death & disease Vol. 16; no. 1; pp. 448 - 15
• Main Authors: Ye, Shengtao, Chen, Junxin, Zheng, Ying, He, Mengmeng, Zhang, Yanqiu, Cheng, Yang, Leng, Yingrong, Wu, Enyi, Kong, Lingyi, Zhang, Hao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.06.2025; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/109; 13/51; 13/89; 14/19; 14/35; 38/90; 631/67/1059/2326; 631/80/458; 64/60; 82/81; 82/83; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cancer; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell Culture; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Enzymatic activity; Enzymes; Ferroptosis; Ferroptosis - drug effects; Hepatocellular carcinoma; Humans; Immunology; Interferon regulatory factor 3; Life Sciences; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice; Mice, Nude; Nuclear Receptor Coactivators - genetics; Nuclear Receptor Coactivators - metabolism; Phenylurea Compounds; Pyridines; Sorafenib - pharmacology; Ubiquitin Thiolesterase - antagonists & inhibitors; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Ubiquitin-specific proteinase; USP18 protein
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-025-07772-0

Targeted therapy resistance has become a major challenge for hepatocellular carcinoma (HCC) treatment. Triggering ferroptosis emerges as a promising strategy to overcome therapeutic resistance. Here, we have identified ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating enzyme family, contributing to HCC resistance by inhibiting sorafenib-induced ferroptosis. Nuclear receptor coactivator 4 (NCOA4), a crucial regulator of ferroptosis, turned out to be a novel downstream effector of USP18 and is posttranslationally suppressed. Such regulation is based on the USP18-mediated deISGylation and degradation process. Additionally, we have demonstrated that sorafenib promotes USP18 accumulation in HCC via the STING/IRF3/ISG15 axis. Importantly, we screened and identified hyperoside (HYP) as a new USP18 enzyme activity inhibitor, which sensitizes cancer cells to existing targeted therapies (sorafenib and regorafenib) by inhibiting USP18 and following deISGylation of NCOA4. Collectively, our study has uncovered a novel mechanism of acquired sorafenib resistance and offers a promising combination therapy strategy for overcoming therapeutic resistance in HCC.