ArticleCell death & disease2024
DDX5 deficiency drives non-canonical NF-κB activation and NRF2 expression, influencing sorafenib response and hepatocellular carcinoma progression.
Article in Cell death & disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Autocrine Control of CD276 by SPARC in Liver Cancer and Its Contribution to Immune Escape and Resistance to Immunotherapy: Elucidating How SPARC Shapes the Tumor Microenvironment and Undermines the Response to Immune Checkpoint Inhibition.Journal of biochemical and molecular toxicology · 2026Article
- Ferroptosis regulatory networks as therapeutic sensitizers in combination therapy for hepatocellular carcinoma (Review).Oncology letters · 2026Review
- Wnt/β-catenin signaling in hepatocellular carcinoma: a key player in resistance to targeted and immunotherapies.Carcinogenesis · 2026Review
- Targeting taurine metabolism via PROTAC-mediated SLC6A6 degradation potentiates photodynamic therapy and reverses immunosuppression in cholangiocarcinoma.Journal of nanobiotechnology · 2026Article
- NF-κB signaling in hepatocellular carcinoma: Mechanisms of tumor progression, immune evasion, and therapeutic resistance.Translational oncology · 2026Review
- DDX17-mediated raptor-dependent mTORC1 activation links autophagy inhibition and metabolic compensation in HCC development.Cellular & molecular biology letters · 2026Article
- The oncogenic microRNA miR-222 promotes human LINE-1 retrotransposition.RNA biology · 2025Article
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Authors and funding
9 authors.
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Abstract
In advanced hepatocellular carcinoma (HCC), RNA helicase DDX5 regulates the Wnt/β-catenin-ferroptosis axis, influencing the efficacy of the multi-tyrosine kinase inhibitor (mTKI) sorafenib. DDX5 inhibits Wnt/β-catenin signaling, preventing sorafenib-induced ferroptosis escape. Sorafenib/mTKIs reduce DDX5 expression, correlating with poor patient survival post-sorafenib treatment. Notably, DDX5-knockout in HCC cells activates Wnt/β-catenin signaling persistently. Herein, we investigate the mechanistic impact of Wnt/β-catenin activation resulting from DDX5 downregulation in the progression and treatment of HCC. RNAseq analyses identified shared genes repressed by DDX5 and upregulated by sorafenib, including Wnt signaling genes, NF-κB-inducing kinase (NIK) essential for non-canonical NF-κB (p52/RelB) activation, and cytoprotective transcription factor NRF2. We demonstrate, Wnt/β-catenin activation induced NIK transcription, leading to non-canonical NF-κB activation, which subsequently mediated NRF2 transcription. Additionally, DDX5 deficiency extended NRF2 protein half-life by inactivating KEAP1 through p62/SQSTM1 stabilization. In a preclinical HCC mouse model, NRF2 knockdown or DDX5 overexpression restricted tumor growth upon sorafenib treatment, via induction of ferroptosis. Importantly, DDX5-knockout HCC cells exhibited elevated expression of Wnt signaling genes, NIK, p52/RelB, and NRF2-regulated genes, regardless of sorafenib treatment. Transcriptomic analyses of HCCs from TCGA and the Stelic Animal Model (STAM) of non-alcoholic steatohepatitis revealed elevated expression of these interconnected pathways in the context of DDX5 downregulation. In conclusion, DDX5 deficiency triggers Wnt/β-catenin signaling, promoting p52/RelB and NRF2 activation, thereby enabling ferroptosis evasion upon sorafenib treatment. Similarly, independent of sorafenib, DDX5 deficiency in liver tumors enhances activation and gene expression of these interconnected pathways, underscoring the clinical relevance of DDX5 deficiency in HCC progression and therapeutic response.
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