ArticleJournal of advanced research2025
Oncogenic cholesterol rewires lipid metabolism in hepatocellular carcinoma via the CSNK2A1-IGF2R Ser2484 axis.
Article in Journal of advanced research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Peptide Drugs in Gastrointestinal Tumors: Integrating Targeting, Delivery, and Therapeutic Actions for Synergistic Strategies.Biomolecules · 2026Review
- Cholesterol metabolic rewiring shapes immune remodeling across hepatocarcinogenesis.Frontiers in immunology · 2026Review
- Oxidative Stress and Reprogramming of Lipid Metabolism in Cancers.Antioxidants (Basel, Switzerland) · 2025Review
- Proteomic Characterization of Liver Cancer Cells Treated with Clinical Targeted Drugs for Hepatocellular Carcinoma.Biomedicines · 2025Article
- The U-Shaped Association Between Remnant Cholesterol and Postoperative Survival in Hepatocellular Carcinoma: Development and Validation of an Interpretable Machine Learning Model.Journal of hepatocellular carcinoma · 2025Article
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Authors and funding
17 authors.
Funding
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Abstract
introductionAlcohol consumption and hepatitis B virus (HBV) infection are common risk factors for hepatocellular carcinoma (HCC). However, few studies have focused on elucidating the mechanisms of HCC with combined alcohol and HBV etiology.
objectivesWe aimed to investigate the molecular features of alcohol and HBV on HCC and to seek out potential therapeutic strategies.
methodsTwo independent cohorts of HCC patients (n = 539 and n = 140) were included to investigate HCC with synergetic alcohol and HBV (AB-HCC) background. Patient-derived cell lines, organoids, and xenografts were used to validate the metabolic fragile. High-throughput drug screening (1181 FDA-approved anticancer drugs) was leveraged to explore the potential therapeutic agents.
resultsHere, we delineated AB-HCC as a distinctive metabolic subtype, hallmarked by oncogenic cholesterol, through the integration of clinical cohorts, proteomics, phosphoproteomics, and spatial transcriptome. Mechanistically, our findings revealed that cholesterol directly binds to CSNK2A1 (Casein Kinase 2 Alpha 1), augmenting its kinase activity and leading to phosphorylation of IGF2R (Insulin-Like Growth Factor 2 Receptor) at Ser2484. This cascade rewires lipid-driven mitochondrial oxidative phosphorylation, spawns reactive oxygen species measured by malondialdehyde assay, and perpetuates a positive feedback loop for cholesterol biosynthesis, ultimately culminating in tumorigenesis. Initial transcriptional activation of CSNK2A1 is driven by upregulation of RAD21 in AB-HCC. Our cholesterol profiling exposes AB-HCC's compensatory mechanism of AB-HCC, which capitalizes on both uptake and biosynthesis of cholesterol to confer survival edge. Moreover, high-throughput drug screening coupled with in vivo validation has uncovered the susceptibilities of AB-HCC, which can be effectively addressed by a combination of dietary cholesterol restriction and oral administration of Fostamatinib. The CSNK2A1-mediated cholesterol biosynthesis pathway has been implicated in various cancers characterized by cholesterol metabolism.
conclusionThese findings not only pinpoint the oncogenic metabolite cholesterol as a hidden culprit in AB-HCC subtype, but also enlighten a novel combination strategy to rejuvenate tumor metabolism.
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