索拉非尼耐药严重降低了晚期肝细胞癌（HCC）患者的治疗效果，但其潜在机制尚未彻底了解。全反式维甲酸（ATRA），一种抗白血病药物，因其对其他抗癌治疗的敏感性而引起了广泛关注。我们的目标是研究ATRA和索拉非尼在HCC上的联合效应及其基本机制。使用CCK-8、细胞球形成、转膜迁移和划痕愈合试验分析了体外HCC细胞的生物学行为。进行Western blotting和qRT-PCR分析，测定PAK1和磷酸化PAK1（pPAK1）的表达。建立异种移植模型以确认ATRA和索拉非尼之间的协同效应。利用TUNEL技术和免疫组化法确定肿瘤组织中的凋亡、增殖、PAK1和pPAK1水平。我们观察到PAK1在HCC中过度表达，其表达与患者的生存率呈负相关。PAK1促进了HCC细胞的增殖、自我更新和上皮间质转变。相关分析表明，索拉非尼的IC50与HCC细胞系中pPAK1水平呈正相关。ATRA通过下调PAK1抑制了HCC的进展，并使HCC对索拉非尼的响应产生敏感性，这一结果可由药物相互作用系数和异种移植模型所获得的数据证实。我们的发现表明，与单独使用索拉非尼相比，ATRA和索拉非尼的联合治疗对于HCC患者来说更具疗效。视频摘要。© 2023. BioMed Central Ltd., Springe Nature的一部分。

Sorafenib resistance greatly reduces the efficacy of treatments in advanced hepatocellular carcinoma (HCC) patients, but the underlying mechanisms are not thoroughly understood. All-trans retinoic acid (ATRA), an anti-leukaemia agent, has attracted considerable attention due to its role in sensitizing cells to other anticancer treatments. We aimed to investigate the combined effect of ATRA and Sorafenib on HCC and the underlying mechanisms.CCK-8, cell sphere formation, trans-well migration, and wound-healing assays were used to analyse the biological behaviours of HCC cells in vitro. Western blotting and qRT-PCR analysis were conducted to measure the expression of p21 activated kinase 1 (PAK1) and phospho-p21 activated kinase 1 (pPAK1). Xenograft models were established to confirm the synergistic effects of ATRA and Sorafenib in vivo. TUNEL assays and immunohistochemistry were utilized to determine apoptosis, proliferation, PAK1 and pPAK1 levels in tumour tissues.We observed that PAK1 was overexpressed in HCC, and its expression was negatively correlated with the survival of patients. PAK1 promoted the proliferation, self-renewal and epithelial-mesenchymal transition of HCC cells. Correlation analysis indicated that the IC50 of Sorafenib was positively correlated with the level of pPAK1 in HCC cell lines. ATRA inhibited the progression of HCC and sensitized HCC response to Sorafenib by downregulation of PAK1, as shown by the calculated coefficient of drug interaction and the data obtained from xenograft models.Our findings indicated that instead of treatment with Sorafenib alone, the combination of ATRA and Sorafenib provides a more effective treatment for HCC patients. Video Abstract.© 2023. BioMed Central Ltd., part of Springer Nature.