ArticleCell death & disease2025
Targeting USP18 overcomes acquired resistance in hepatocellular carcinoma by regulating NCOA4 deISGylation and ferroptosis.
Article in Cell death & disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Global research landscape and hotspots of paraptosis: a multi-database bibliometric analysis with a focused literature review.Frontiers in oncology · 2026Pooled it
- Transcription factor EN1 governs a lipogenic USP18-ACLY axis to drive bladder cancer malignancy.Oncogene · 2026Article
- Cancer drug response and resistance: molecular mechanisms and combating strategies.Signal transduction and targeted therapy · 2026Review
- Synergistic mechanisms and clinical translation of regorafenib combination therapies.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Deubiquitinating enzymes-mediated post-translational modifications of ferroptosis regulates cancer drug resistance.Discover oncology · 2026Review
- Deubiquitinases at the crossroads of ferroptosis and cancer therapy: mechanisms and therapeutic potential.Molecular biology reports · 2026Review
- Decoding the spatiotemporal characteristics of ferroptosis: reshaping tumour therapeutic strategies.Experimental hematology & oncology · 2026Review
- Post-Translational Modification Networks in Ferroptosis: Orchestrating Defense, Drug Resistance, and Therapeutic Opportunities in Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2026Review
- ANP32A interacts with LDHA to modulate glycolysis and ferroptosis in hepatocellular carcinoma.Frontiers in oncology · 2026Article
- Post-translational modification in hepatocellular carcinoma resistance: molecular mechanisms and therapeutic targeting.Frontiers in immunology · 2026Review
- Bioengineered Exosome-Magnetic Nanoplatform for Precision Therapy of Hepatocellular CarcinomaInternational journal of nanomedicine · 2026Article
- Targeting ferroptosis and cuproptosis in gastrointestinal cancers: molecular mechanisms, metabolic vulnerabilities, and therapeutic interventions.Molecular biomedicine · 2025Review
- Knockdown of TOP2A reverses cisplatin resistance in ovarian cancer by inhibiting EMT via ferroptosis mediated by the TP53/GPX4/SLC7A11 axis.Frontiers in immunology · 2025Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
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.
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