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Updated: May 11, 2026
Revealing the Ferroptotic Phenotype of Medulloblastoma
Published on: March 15, 2024
Targeting the USP5-HSPB1 axis overcomes ferroptosis resistance in intrahepatic cholangiocarcinoma
Chengbin He1, Lvyuan Li2, Yani Pan3
1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, MOE Innovation Center for Basic Research in Tumor Immunotherapy, Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei 230001, China.
Abstract:
Ferroptosis evasion contributes to therapeutic resistance in intrahepatic cholangiocarcinoma (ICC), yet the ubiquitin-dependent mechanisms governing this process remain poorly defined. Here, we identify ubiquitin-specific protease 5 (USP5) as a clinically relevant ferroptosis suppressor in ICC. USP5 was frequently upregulated in human ICC specimens, and elevated USP5 expression was associated with adverse clinicopathological features and poor outcomes. Mechanistically, USP5 directly interacted with heat shock protein beta-1 (HSPB1) and stabilizes HSPB1 by deubiquitination, thereby attenuating lipid peroxidation-driven ferroptosis. USP5 depletion destabilizes HSPB1, sensitizes ICC cells to ferroptosis, and limits tumor growth, whereas USP5 overexpression promotes ferroptosis resistance and tumor progression. Structure-guided virtual screening and functional validation identified hellebrigenol (Hel) as a candidate USP5 inhibitor that increases HSPB1 ubiquitination and proteasome-dependent turnover, inducing ferroptosis and suppressing ICC progression. Notably, Hel potentiated gemcitabine efficacy, resulting in pronounced tumor inhibition and improved survival. Collectively, these findings establish the USP5-HSPB1 axis as a ferroptosis checkpoint in ICC and suggest pharmacologic USP5 inhibition as a strategy to improve chemotherapy response.
Insights
Ubiquitin-specific protease 5 (USP5) suppresses ferroptosis in intrahepatic cholangiocarcinoma (ICC). Inhibiting USP5 with hellebrigenol resensitizes ICC cells to ferroptosis and enhances chemotherapy, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Ferroptosis evasion is a key mechanism of therapeutic resistance in intrahepatic cholangiocarcinoma (ICC).
- The specific ubiquitin-dependent pathways controlling ferroptosis in ICC are not well understood.
- Identifying novel targets is crucial for overcoming treatment resistance in ICC.
Purpose of the Study:
- To identify novel regulators of ferroptosis in ICC.
- To investigate the role of ubiquitin-specific protease 5 (USP5) in ICC ferroptosis.
- To explore hellebrigenol (Hel) as a potential therapeutic agent targeting USP5 in ICC.
Main Methods:
- Analysis of USP5 expression in human ICC specimens.
- In vitro studies involving USP5 depletion and overexpression in ICC cells.
- Biochemical assays to determine USP5-HSPB1 interaction and deubiquitination activity.
- Structure-guided virtual screening to identify USP5 inhibitors.
- In vivo studies using hellebrigenol in ICC models.
- Combination therapy studies with gemcitabine.
Main Results:
- USP5 is upregulated in ICC and associated with poor prognosis.
- USP5 stabilizes heat shock protein beta-1 (HSPB1) via deubiquitination, inhibiting ferroptosis.
- USP5 depletion sensitizes ICC cells to ferroptosis and reduces tumor growth.
- Hellebrigenol inhibits USP5, promoting HSPB1 ubiquitination and degradation, inducing ferroptosis.
- Hellebrigenol potentiates gemcitabine efficacy, inhibiting tumor progression and improving survival.
Conclusions:
- The USP5-HSPB1 axis acts as a critical ferroptosis checkpoint in ICC.
- Pharmacologic inhibition of USP5 is a promising strategy to overcome ferroptosis resistance in ICC.
- Hellebrigenol represents a potential therapeutic agent for ICC, enhancing chemotherapy response.
