膜蛋白表达失调与肿瘤发生和进展有关，包括肝细胞癌（HCC）。在这项研究中，我们的目的是鉴定调节 HCC 活力的膜蛋白。为了实现这一目标，我们针对编码膜相关蛋白的人类基因进行了 CRISPR 激活筛选，揭示了 TMX2 作为 HCC 细胞活力的潜在驱动因素。功能获得和丧失实验表明，TMX2 促进 HCC 的生长和肿瘤发生。临床上，TMX2是HCC患者的独立预后因素。它在 HCC 组织中显着上调，并与 HCC 患者的不良预后相关。从机制上讲，TMX2 通过促进 KPNB1 核输出和 TFEB 核输入来促进巨自噬/自噬。此外，TMX2 与 VDAC2 和 VADC3 相互作用，协助将 PRKN 募集到有缺陷的线粒体，以促进氧化应激期间的细胞保护性线粒体自噬。最有趣的是，HCC 细胞通过上调 TMX2 表达和细胞自噬来应对氧化应激。 TMX2 的敲低增强了乐伐替尼的抗肿瘤作用。总之，我们的研究结果强调了 TMX2 通过促进自噬和线粒体自噬来驱动 HCC 细胞活力的关键作用。这些结果表明 TMX2 可能作为 HCC 治疗的预后标志物和有希望的治疗靶点。

The dysregulation of membrane protein expression has been implicated in tumorigenesis and progression, including hepatocellular carcinoma (HCC). In this study, we aimed to identify membrane proteins that modulate HCC viability. To achieve this, we performed a CRISPR activation screen targeting human genes encoding membrane-associated proteins, revealing TMX2 as a potential driver of HCC cell viability. Gain- and loss-of-function experiments demonstrated that TMX2 promoted growth and tumorigenesis of HCC. Clinically, TMX2 was an independent prognostic factor for HCC patients. It was significantly upregulated in HCC tissues and associated with poor prognosis of HCC patients. Mechanistically, TMX2 was demonstrated to promote macroautophagy/autophagy by facilitating KPNB1 nuclear export and TFEB nuclear import. In addition, TMX2 interacted with VDAC2 and VADC3, assisting in the recruitment of PRKN to defective mitochondria to promote cytoprotective mitophagy during oxidative stress. Most interestingly, HCC cells responded to oxidative stress by upregulating TMX2 expression and cell autophagy. Knockdown of TMX2 enhanced the anti-tumor effect of lenvatinib. In conclusion, our findings emphasize the pivotal role of TMX2 in driving the HCC cell viability by promoting both autophagy and mitophagy. These results suggest that TMX2 May serve as a prognostic marker and promising therapeutic target for HCC treatment.