ArticleScience China. Life sciences2022
CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma: a cross-talk between FGF21 and the NRF2 pathway.
Article in Science China. Life sciences, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- CRISPR-Cas9 in Cancer Therapy: Overcoming Delivery Barriers and Off-Target Effects for Clinical Translation.Health science reports · 2026Article
- Review
- A Novel MPT-Driven Necrosis-Related lncRNA Signature for Prognostic Prediction in Hepatocellular Carcinoma: Validation Using Organoids.Cancer medicine · 2026Article
- FGF19 in Solid Tumors: Molecular Mechanisms, Metabolic Reprogramming, and Emerging Therapeutic Opportunities.Theranostics · 2026Review
- Nrf2/Keap1 Signaling Axis in the Brain: Master Regulator of Oxidative Stress in Neurodegenerative and Psychiatric Disorders.Molecular neurobiology · 2025Review
- RIOK1 phase separation restricts PTEN translation via stress granules activating tumor growth in hepatocellular carcinoma.Nature cancer · 2025Article
- Bridging systemic metabolic dysfunction and Alzheimer's disease: the liver interface.Molecular neurodegeneration · 2025Review
- Serum FGF21 as a predictor of response to atezolizumab and bevacizumab in HCC.JHEP reports : innovation in hepatology · 2025Article
- Circulating Fibroblast Growth Factor 21 (FGF21) as a Prognostic and Diagnostic Biomarker in Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2025Article
- The USP11/Nrf2 positive feedback loop promotes colorectal cancer progression by inhibiting mitochondrial apoptosis.Cell death & disease · 2024Article
- FGF21-mediated autophagy: Remodeling the homeostasis in response to stress in liver diseases.Genes & diseases · 2024Review
- CircMYBL2 facilitates hepatocellular carcinoma progression by regulating E2F1 expression.Oncology research · 2024Article
- A review of the literature on the use of CRISPR/Cas9 gene therapy to treat hepatocellular carcinoma.Oncology research · 2024Review
- Research progress and application of the CRISPR/Cas9 gene-editing technology based on hepatocellular carcinoma.Asian journal of pharmaceutical sciences · 2023Review
- Identifying CDC7 as a synergistic target of chemotherapy in resistant small-cell lung cancer via CRISPR/Cas9 screening.Cell death discovery · 2023Article
- Genome-wide CRISPR/Cas9 screening for drug resistance in tumors.Frontiers in pharmacology · 2023Review
- Hepatic FGF21: Its Emerging Role in Inter-Organ Crosstalk and Cancers.International journal of biological sciences · 2022Review
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The treatment of hepatocellular carcinoma (HCC) has been dominated by multikinase inhibitors for more than a decade. However, drug resistance can severely restrict the efficacy of these drugs. Using CRISPR/CAS9 genome library screening, we evaluated Kelch-like ECH-associated protein 1 (KEAP1) as a key regulator of sorafenib's susceptibility in HCC. We also investigated whether KEAP1's knockdown can stabilize nuclear factor (erythroid-derived 2)-like 2 (NRF2) protein levels that led to sorafenib's resistance, including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC's growth in vitro and in vivo. Furthermore, we clarified that fibroblast growth factor 21 (FGF21) is an important downstream regulator of NRF2 in HCC. Intriguingly, we observed that FGF21 bound to NRF2 through the C-terminus of FGF21, thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC. These findings, therefore, propose that targeting FGF21 is a promising strategy to combat HCC sorafenib's resistance.
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