肝细胞癌（HCC）是一种普遍存在的侵袭性恶性肿瘤，具有高复发和转移风险。肝癌干细胞（CSC）越来越被认为是这些过程的关键驱动因素。在我们之前的研究中，我们证明了TFCP2L1参与维持胚胎干细胞的多能性。然而，其与肝脏 CSC 的相关性仍有待探索。在这项研究中，我们报告了 HCC 组织中 TFCP2L1 蛋白水平与患者预后之间的负相关。 TFCP2L1 的敲低显着降低了 HCC 细胞的增殖、侵袭、转移、克隆形成和球体形成能力，而其过表达则增强了这些功能。此外，使用裸鼠模型的实验证实了 TFCP2L1 在肝脏 CSC 功能和致瘤潜力中的重要作用。从机制上讲，我们发现TFCP2L1通过上调NANOG促进CSC的干性，随后激活JAK/STAT3通路，从而促进HCC发病机制。重要的是，我们鉴定了一种针对 TFCP2L1 活性结构域的特定小分子，该小分子与索拉非尼联合使用，可使肝癌细胞对治疗敏感。总之，这些发现强调了 TFCP2L1 在 HCC 进展中的病理意义，支持其作为该疾病的预后生物标志物和治疗靶点的潜力。© 2024。作者。

Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy associated with high risks of recurrence and metastasis. Liver cancer stem cells (CSCs) are increasingly recognized as pivotal drivers of these processes. In our previous research, we demonstrated the involvement of TFCP2L1 in maintaining the pluripotency of embryonic stem cells. However, its relevance to liver CSCs remains unexplored. In this study, we report an inverse correlation between TFCP2L1 protein levels in HCC tissue and patient outcomes. The knockdown of TFCP2L1 significantly reduced HCC cell proliferation, invasion, metastasis, clonal formation, and sphere-forming capacity, while its overexpression enhanced these functions. In addition, experiments using a nude mouse model confirmed TFCP2L1's essential role in liver CSCs' function and tumorigenic potential. Mechanistically, we showed that TFCP2L1 promotes the stemness of CSCs by upregulating NANOG, which subsequently activates the JAK/STAT3 pathway, thereby contributing to HCC pathogenesis. Importantly, we identified a specific small molecule targeting TFCP2L1's active domain, which, in combination with Sorafenib, sensitizes hepatoma cells to treatment. Together, these findings underscore TFCP2L1's pathological significance in HCC progression, supporting its potential as a prognostic biomarker and therapeutic target in this disease.© 2024. The Author(s).