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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics

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

Shengtao Ye1, Junxin Chen1, Ying Zheng1

  • 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.

Cell Death & Disease
|June 13, 2025
PubMed

Insights

Ubiquitin-specific protease 18 (USP18) drives hepatocellular carcinoma (HCC) resistance by blocking ferroptosis. Inhibiting USP18 with hyperoside (HYP) resensitizes HCC cells to targeted therapies, offering a new treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Targeted therapy resistance is a significant hurdle in treating hepatocellular carcinoma (HCC).
  • Ferroptosis induction presents a promising approach to overcome this resistance.
  • Understanding resistance mechanisms is crucial for developing effective HCC treatments.

Purpose of the Study:

  • To identify mechanisms of sorafenib resistance in HCC.
  • To investigate the role of ubiquitin-specific protease 18 (USP18) in ferroptosis regulation.
  • To explore novel therapeutic strategies for overcoming HCC resistance.

Main Methods:

  • Investigated the role of USP18 in sorafenib-induced ferroptosis in HCC.
  • Identified Nuclear receptor coactivator 4 (NCOA4) as a downstream effector of USP18.
  • Elucidated the USP18-mediated deISGylation and degradation pathway.
  • Examined the STING/IRF3/ISG15 axis in sorafenib-induced USP18 accumulation.
  • Screened for USP18 inhibitors and evaluated their efficacy in combination therapy.

Main Results:

  • USP18 was found to inhibit sorafenib-induced ferroptosis in HCC.
  • USP18 post-translationally suppresses NCOA4 via deISGylation and degradation.
  • Sorafenib promotes USP18 accumulation through the STING/IRF3/ISG15 pathway.
  • Hyperoside (HYP) was identified as a USP18 inhibitor.
  • HYP sensitized HCC cells to sorafenib and regorafenib by inhibiting USP18 and NCOA4 deISGylation.

Conclusions:

  • A novel mechanism of acquired sorafenib resistance involving USP18-mediated ferroptosis inhibition was uncovered.
  • USP18 is a key regulator of ferroptosis in HCC and a potential therapeutic target.
  • Hyperoside represents a promising agent for combination therapy to overcome targeted therapy resistance in HCC.

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