Background: Alcohol consumption increases the risk of hepatocellular carcinoma (HCC), and associated with a high mortality rate and poor prognosis. N6-methyladenosine (m6A) methylations play key roles in tumorigenesis and progression. However, our current knowledge about m6A in alcohol-related HCC (A-HCC) remains elucidated. Herein, the authors construct an integrative m6A model based on A-HCC subtyping and mechanism exploration workflow./nMethods: Based on the m6A expressions of A-HCC and in vivo experiment, different prognosis risk A-HCC subtypes are identified. Meanwhile, multiple interdependent indicators of prognosis including patient survival rate, clinical pathological prognosis and immunotherapy sensitivity./nResults: The m6A model includes LRPPRC, YTHDF2, KIAA14219, and RBM15B, classified A-HCC patients into high/low-risk subtypes. The high-risk subtype compared to the low-risk subtype showed phenotypic malignancy, poor prognosis, immunosuppression, and activation of tumorigenesis and proliferation-related pathways, including the E2F target, DNA repair, and mTORC1 signalling pathways. The expression of Immunosuppressive cytokines DNMT1/EZH2 was up-regulated in A-HCC patients, and teniposide may be a potential therapeutic drug for A-HCC./nConclusion: Our model redefined A-HCC prognosis risk, identified potential m6As linking tumour progress and immune regulations and selected possible therapy target, thus promoting understanding and clinical applications about A-HCC.

中文翻译：

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基于综合 N6-甲基腺苷甲基化模型的酒精相关性肝细胞癌预后亚型的识别和表征


背景：饮酒会增加肝细胞癌（HCC）的风险，并与高死亡率和不良预后相关。 N6-甲基腺苷 (m6A) 甲基化在肿瘤发生和进展中发挥关键作用。然而，我们目前对酒精相关性 HCC (A-HCC) 中 m6A 的了解仍不清楚。在此，作者构建了基于A-HCC亚型分型和机制探索工作流程的综合m6A模型。/n方法：基于A-HCC的m6A表达和体内实验，鉴定不同预后风险的A-HCC亚型。同时，多个相互依赖的预后指标包括患者生存率、临床病理预后和免疫治疗敏感性。/n结果： m6A模型包括LRPPRC、YTHDF2、KIAA14219和RBM15B，将A-HCC患者分为高/低风险亚型。与低风险亚型相比，高风险亚型表现出表型恶性、预后不良、免疫抑制以及肿瘤发生和增殖相关通路的激活，包括E2F靶点、DNA修复和mTORC1信号通路。 A-HCC 患者中免疫抑制细胞因子 DNMT1/EZH2 的表达上调，替尼泊苷可能是 A-HCC 的潜在治疗药物。/n结论：我们的模型重新定义了 A-HCC 预后风险，确定了与肿瘤进展相关的潜在 m6As免疫调节并选择可能的治疗靶点，从而促进对A-HCC的认识和临床应用。