尽管近年来肝细胞癌（HCC）的治疗取得了实质性突破，但许多患者在诊断时已处于中晚期，无法进行手术切除。因此，寻找HCC的有效治疗靶点具有重要意义。本研究基于单细胞RNA测序发现间隙连接蛋白β-2（GJB2）在恶性细胞中高度富集，GJB2表达越高表明预后越差。与正常肝组织相比，GJB2 在 HCC 癌细胞中的定位发生了变化。在癌细胞中，GJB2往往位于细胞质和细胞核中，而在正常组织中，GJB2主要位于细胞膜上。 GJB2与糖酵解相关，通过诱导IκBa泛素化降解促进NF-κB通路，激活HIF-1α/GLUT-1/PD-L1通路。此外，GJB2敲低重塑肿瘤免疫微环境，丹酚酸B抑制GJB2活性。总之，GJB2 通过细胞质易位激活糖酵解并产生抑制性肿瘤微环境，从而促进 HCC 进展。丹酚酸 B 抑制 GJB2 的表达并增强抗 PD1 治疗的敏感性，这可能为 HCC 新型联合治疗策略的开发提供见解。© 2024 作者。 《Advanced Science》由 Wiley‐VCH GmbH 出版。

Despite substantial breakthroughs in the treatment of hepatocellular carcinoma (HCC) in recent years, many patients are diagnosed in the middle or late stages, denying them the option for surgical excision. Therefore, it is of great importance to find effective therapeutic targets of HCC. In this study, it is found that Gap junction protein beta-2 (GJB2) is highly enriched in malignant cells based on single-cell RNA sequencing and higher expression of GJB2 indicates a worse prognosis. The localization of GJB2 in HCC cancer cells is changed compared with normal liver tissue. In cancer cells, GJB2 tends to be located in the cytoplasm and nucleus, while in normal tissues, GJB2 is mainly located on the cell membrane. GJB2 is related to glycolysis, promoting NF-κB pathway via inducing the ubiquitination degradation of IκBa, and activating HIF-1α/GLUT-1/PD-L1 pathway. In addition, GJB2 knockdown reshapes tumor immune microenvironment and Salvianolic acid B inhibits the activity of GJB2. In conclusion, GJB2 promotes HCC progression by activating glycolysis through cytoplasmic translocation and generating a suppressive tumor microenvironment. Salvianolic acid B inhibits the expression of GJB2 and enhances the sensitivity of anti-PD1 therapy, which may provide insights into the development of novel combination therapeutic strategies for HCC.© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.