语法素蛋白-6（Syntaxin-6，简称STX6）是一种位于转高尔基体网络中的语法素家族蛋白质，参与多种细胞内膜运输事件。STX6在不同的人类恶性肿瘤中有过表达。然而，关于STX6在肝细胞癌（HCC）中的确切功能和分子机制，目前所知甚少。在该研究中，我们发现STX6在HCC组织中的表达显著增加，并与不良生存率相关。功能增强和功能缺失实验表明，STX6促进了HCC细胞的体外和体内增殖和转移。在分子机制上，STX6受上游刺激因子2（USF2）的负调节。此外，STX6促进自噬泡与溶酶体的结合。重要的是，我们证明，STX6过表达虽然增强了对lenvatinib的耐药性，但对自噬活化剂rapamycin使HCC细胞敏感。该研究揭示了在USF2的控制下，STX6通过促进自噬通量加速了微管相关蛋白1轻链3 beta（LC3）的降解，最终促进了HCC的进展。总体而言，我们建议USF2-STX6-LC3B轴是肝癌的潜在治疗靶点。© 作者。

Syntaxin-6 (STX6), a protein of the syntaxin family, is located in the trans-Golgi network and is involved in a variety of intracellular membrane transport events. STX6 is overexpressed in different human malignant tumors. However, little is known about its exact function and molecular mechanism in hepatocellular carcinoma (HCC). In this study, we found that the expression of STX6 was significantly increased in HCC tissues and was associated with poor survival. Gain- and loss-of-function experiments showed that STX6 promotes cell proliferation and metastasis of HCC cells both in vitro and in vivo. Mechanistically, STX6 was negatively regulated by the upstream stimulatory factor 2 (USF2). In addition, STX6 facilitates the association of autophagosomes with lysosomes. Importantly, we demonstrated that STX6 overexpression, despite enhanced resistance to lenvatinib, sensitizes HCC cells to the autophagy activator rapamycin. This study revealed that, under the control of USF2, STX6 accelerates the degradation of microtubule-associated protein 1 light chain 3 beta (LC3) by promoting autophagic flux, ultimately promoting HCC progression. Collectively, we suggest that the USF2-STX6-LC3B axis is a potential therapeutic target in liver cancer.© The author(s).