ArticleJournal of experimental & clinical cancer research : CR2022
Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma.
Article in Journal of experimental & clinical cancer research : CR, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 134 papers.
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Who cites it
134 citing papers in PubMed, 203 citations in OpenAlex.
- Metformin Inhibits Ferroptotic Cell Death by Suppressing Cysteine Deprivation-Induced Mitochondrial Dysfunction.Pharmacology research & perspectives · 2026Article
- Lapatinib suppresses cysteine deprivation-induced ferroptotic cell death by modulating mitochondrial function.Medical oncology (Northwood, London, England) · 2026Article
- Ferroptosis and aging: Inducing and catalyzing neurodegenerative diseases.Neural regeneration research · 2026Article
- Single-cell and bulk transcriptomic profiling of metabolism-related lncRNAs reveals tumor heterogeneity and prognostic markers in non-small cell lung cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Article
- TRIM27-Cas9-loaded EVs suppress HCC proliferation and enhance responsiveness to anti-PD-1 therapy by promoting ACSL4-mediated ferroptosis.Cell death and differentiation · 2026Article
- ACSL4 in Alzheimer's disease: Pathogenetic mechanisms and potential therapeutic targets.Genes & diseases · 2026Review
- Targeting ferroptosis induction via nanomaterials in hepatocellular carcinoma: an insight into mechanism and therapeutic potential.Journal of nanobiotechnology · 2026Review
- Targeting programmed cell death: a novel therapeutic paradigm for cancer based on mode-of-death classification.Apoptosis : an international journal on programmed cell death · 2026Review
- Non-coding RNAs as master regulators of ferroptosis in cancer: mechanisms and clinical implications.Molecular cancer · 2026Review
- GPR40 Attenuates Glioma TMZ-Resistance Through Ferroptosis Inhibition.Neurochemical research · 2026Article
- Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.Molecular biomedicine · 2026Review
- Atherosclerotic plaque-derived extracellular vesicles mediate smooth muscle cell phenotypic switching and promote vascular remodeling : EVs promote VSMC phenotypic switching.Cellular and molecular life sciences : CMLS · 2026Article
- Ferroptosis: The dawn of reversing drug resistance in digestive cancers.Genes & diseases · 2026Review
- Mechanisms of the RGS12-GPX4-ACSL4 signaling axis in regulating ferroptosis during myocardial ischemia-reperfusion injury.Journal of anesthesia and translational medicine · 2026Review
- Exploring Cuproptosis-Related Prognostic Signature for Hepatocellular Carcinoma: Bioinformatics and In Vitro Analyses.Digestive diseases and sciences · 2026Article
- Metabolic reprogramming-driven resistance to multi-kinase inhibitors in hepatocellular carcinoma: molecular mechanisms and therapeutic opportunities.Molecular cancer · 2026Review
- Epigenetic and post-translational regulatory networks of ferroptosis in the tumor immune microenvironment.Experimental hematology & oncology · 2026Review
- Semantic-enhanced heterogeneous graph learning for identifying ncRNAs associated with drug resistance.Bioinformatics (Oxford, England) · 2026Article
- ACSL4 as a context-dependent metabolic switch in hepatocellular carcinoma: implications for ferroptosis and immunotherapy.Frontiers in immunology · 2026Review
- Post-Translational Modification Networks in Ferroptosis: Orchestrating Defense, Drug Resistance, and Therapeutic Opportunities in Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2026Review
74 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundDrug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified.
methodsThe clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets.
resultsWe found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3'-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response.
conclusionOur study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients.
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