肝细胞癌（HCC）是癌症死亡的主要原因之一，预后非常差，有效的治疗选择很少。尽管乐伐替尼被批准用于治疗晚期HCC患者，但只有少数患者能够从这种靶向治疗中受益。采用二乙基亚硝胺（DEN）-CCL4小鼠肝肿瘤和异种移植肿瘤模型来评估KDM6A的功能在 HCC 进展中。利用异种移植肿瘤模型和HCC细胞系评估KDM6A在HCC对乐伐替尼药物敏感性中的作用。进行了 RNA-seq 和 ChIP 测定以进行机械研究。我们发现 KDM6A 在 HCC 组织中表现出显着上调，并与不良预后相关。我们进一步证明 KDM6A 敲低可显着抑制体外 HCC 细胞的增殖和迁移。此外，在小鼠肝脏肿瘤模型中，肝脏 Kdm6a 缺失也抑制了肝脏肿瘤的发生。从机制上讲，KDM6A 缺失下调 FGFR4 表达，从而抑制 PI3K-AKT-mTOR 信号通路，导致 HCC 中葡萄糖和脂质代谢重新编程。 HCC标本和小鼠肝肿瘤组织中KDM6A和FGFR4水平呈正相关。值得注意的是，KDM6A 敲低显着抑制了乐伐替尼在体外和体内治疗 HCC 细胞的疗效。我们的研究结果表明，KDM6A 通过激活 FGFR4 表达促进 HCC 进展，可能是影响乐伐替尼在 HCC 治疗中疗效的重要分子。© 2023作者们。约翰·威利出版的《临床与转化医学》

Hepatocellular carcinoma (HCC) is one of the major causes of death from cancer and has a very poor prognosis with few effective therapeutic options. Despite the approval of lenvatinib for the treatment of patients suffering from advanced HCC, only a small number of patients can benefit from this targeted therapy.Diethylnitrosamine (DEN)-CCL4 mouse liver tumour and the xenograft tumour models were used to evaluate the function of KDM6A in HCC progression. The xenograft tumour model and HCC cell lines were used to evaluate the role of KDM6A in HCC drug sensitivity to lenvatinib. RNA-seq and ChIP assays were conducted for mechanical investigation.We revealed that KDM6A exhibited a significant upregulation in HCC tissues and was associated with an unfavourable prognosis. We further demonstrated that KDM6A knockdown remarkably suppressed HCC cell proliferation and migration in vitro. Moreover, hepatic Kdm6a loss also inhibited liver tumourigenesis in a mouse liver tumour model. Mechanistically, KDM6A loss downregulated the FGFR4 expression to suppress the PI3K-AKT-mTOR signalling pathway, leading to a glucose and lipid metabolism re-programming in HCC. KDM6A and FGFR4 levels were positively correlated in HCC specimens and mouse liver tumour tissues. Notably, KDM6A knockdown significantly inhibited the efficacy of lenvatinib therapy in HCC cells in vitro and in vivo.Our findings revealed that KDM6A promoted HCC progression by activating FGFR4 expression and may be an essential molecule for influencing the efficacy of lenvatinib in HCC therapy.© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.