Introduction

Alcohol 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.

Objectives

We aimed to investigate the molecular features of alcohol and HBV on HCC and to seek out potential therapeutic strategies.

Methods

Two 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.

Results

Here, 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.

Conclusion

These 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.

中文翻译：

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致癌胆固醇通过 CSNK2A1-IGF2R Ser2484 轴重新连接肝细胞癌中的脂质代谢

 介绍

饮酒和乙型肝炎病毒 （HBV） 感染是肝细胞癌 （HCC） 的常见危险因素。然而，很少有研究专注于阐明 HCC 与酒精和 HBV 联合病因的机制。

 目标

我们旨在研究酒精和 HBV 对 HCC 的分子特征，并寻找潜在的治疗策略。

 方法

纳入两个独立的 HCC 患者队列 （n = 539 和 n = 140），以研究具有协同酒精和 HBV （AB-HCC） 背景的 HCC。使用患者来源的细胞系、类器官和异种移植物来验证代谢脆弱性。利用高通量药物筛选 （1181 种 FDA 批准的抗癌药物） 来探索潜在的治疗药物。

 结果

在这里，我们通过整合临床队列、蛋白质组学、磷酸化蛋白质组学和空间转录组，将 AB-HCC 描述为一种独特的代谢亚型，以致癌胆固醇为标志。从机制上讲，我们的研究结果显示胆固醇直接与 CSNK2A1 （酪蛋白激酶 2 Alpha 1） 结合，增强其激酶活性并导致 IGF2R （胰岛素样生长因子 2 受体） 在 Ser2484 位点磷酸化。这种级联反应重新连接脂质驱动的线粒体氧化磷酸化，产生通过丙二醛测定法测量的活性氧，并延续胆固醇生物合成的正反馈回路，最终导致肿瘤发生。CSNK2A1 的初始转录激活是由 AB-HCC 中 RAD21 的上调驱动的。我们的胆固醇分析揭示了 AB-HCC 的 AB-HCC 代偿机制，它利用胆固醇的摄取和生物合成来赋予生存优势。此外，高通量药物筛选与体内验证相结合，揭示了 AB-HCC 的易感性，这可以通过膳食胆固醇限制和口服 Fostamatinib 的组合来有效解决。CSNK2A1介导的胆固醇生物合成途径与以胆固醇代谢为特征的各种癌症有关。

 结论

这些发现不仅确定了致癌代谢物胆固醇是 AB-HCC 亚型的隐藏罪魁祸首，而且还为一种使肿瘤代谢恢复活力的新联合策略提供了启示。