含有 17 (KCTD17) 蛋白的钾通道四聚化结构域是 cullin3 (Cul3) 泛素连接酶复合物的接头，与多种人类疾病有关；然而，它在肝细胞癌（HCC）中的作用仍然难以捉摸。在这里，我们旨在阐明KCTD17的临床特征，并研究KCTD17影响HCC进展的机制。我们分析了HCC患者的转录组数据。使用二乙基亚硝胺 (DEN) 治疗肝细胞特异性 KCTD17 缺陷小鼠，以评估其对 HCC 进展的影响。此外，我们测试了 KCTD17 定向反义寡核苷酸的体内治疗潜力。我们的研究表明，与非肿瘤对照相比，HCC 患者和 HCC 小鼠模型的肿瘤中 KCTD17 表达上调。我们鉴定出亮氨酸拉链样转录调节因子 1 (Lztr1) 蛋白（一种先前鉴定的 Ras 去稳定剂）作为 KCTD17-Cul3 复合物的底物。 KCTD17 介导的 Lztr1 降解导致 Ras 稳定，从而增加肝癌细胞的增殖、迁移和伤口愈合。肝细胞特异性 KCTD17 缺陷小鼠或肝癌异种移植模型不太容易发生癌变或肿瘤生长。同样，与对照 ASO 治疗小鼠相比，在 HCC 小鼠模型中使用 KCTD17 定向反义寡核苷酸 (ASO) 治疗可显着降低肿瘤体积和 Ras 蛋白水平。KCTD17 诱导 Ras 和下游信号通路的稳定， HCC 进展可能代表 HCC 的新治疗靶点。

Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression.We analyzed transcriptomic data from patients with HCC. Hepatocyte-specific KCTD17 deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested KCTD17-directed antisense oligonucleotides for their therapeutic potential in vivo.Our investigation revealed the upregulation of KCTD17 expression in both tumors from patients with HCC and mouse models of HCC, in comparison to non-tumor controls. We identified the leucine zipper-like transcriptional regulator 1 (Lztr1) protein, a previously identified Ras destabilizer, as a substrate for KCTD17-Cul3 complex. KCTD17-mediated Lztr1 degradation led to Ras stabilization, resulting in increased proliferation, migration, and wound healing in liver cancer cells. Hepatocyte-specific KCTD17 deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with KCTD17-directed antisense oligonucleotides (ASO) in a mouse model of HCC markedly lowered tumor volume as well as Ras protein levels, compared to those in control ASO-treated mice.KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.