肝细胞癌 (HCC) 是一种高度致命的癌症，蛋白质组学研究表明 HCC 组织中蛋白质多样性和丰度增加，但蛋白质翻译的作用在 HCC 中尚未得到广泛探索。我们的研究重点是翻译过程中的关键分子，以确定 HCC 的潜在贡献者。我们发现 EIF4G2（一种重要的翻译起始因子）在 HCC 组织中显着上调，并与不良预后相关。这项研究独特地强调了 EIF4G2 缺失的影响，它在体外和体内抑制肿瘤生长和转移。此外，多核糖体分析和新生蛋白质合成测定揭示了 EIF4G2 在调节蛋白质翻译中的作用，特别将 PLEKHA1 确定为关键翻译产物。这代表了对 HCC 恶性肿瘤的一种新颖的机制见解。 RNA 免疫沉淀 (RIP) 和双荧光素酶报告基因检测进一步揭示 EIF4G2 通过 IRES 依赖性方式促进 PLEKHA1 翻译。重要的是，EIF4G2 消耗和 PLEKHA1 减少在抑制细胞迁移和侵袭方面的协同作用强调了靶向该轴的治疗潜力。这项研究不仅增进了我们对 HCC 翻译调控的理解，而且还确定了 EIF4G2-PLEKHA1 轴作为一个有前途的治疗靶点，为干预 HCC 治疗提供了新途径。

Hepatocellular carcinoma (HCC) is a highly lethal cancer, and proteomic studies have shown increased protein diversity and abundance in HCC tissues, whereas the role of protein translation has not been extensively explored in HCC. Our research focused on key molecules in the translation process to identify a potential contributor in HCC. We discovered that EIF4G2, a crucial translation initiation factor, is significantly upregulated in HCC tissues and associated with poor prognosis. This study uniquely highlights the impact of EIF4G2 deletion, which suppresses tumor growth and metastasis both in vitro and in vivo. Furthermore, polysome analysis and nascent protein synthesis assays revealed EIF4G2's role in regulating protein translation, specifically identifying PLEKHA1 as a key translational product. This represents a novel mechanistic insight into HCC malignancy. RNA immunoprecipitation (RIP) and Dual-luciferase reporter assays further revealed that EIF4G2 facilitates PLEKHA1 translation via an IRES-dependent manner. Importantly, the synergistic effects of EIF4G2 depletion and PLEKHA1 reduction in inhibiting cell migration and invasion underscore the therapeutic potential of targeting this axis. This study not only advances our understanding of translational regulation in HCC but also identifies the EIF4G2-PLEKHA1 axis as a promising therapeutic target, offering new avenues for intervention in HCC treatment.