The oncogenic potential of chromosome 8q22 copy number gain in liver cancer remains to be depicted. Here, we report that ZNF706, encoded by a gene mapped to chromosome 8q22, is a C2H2-type zinc finger protein. However, the biological function and mechanism of ZNF706 have been poorly investigated. Clinically, ZNF706 expression was elevated in hepatocellular carcinoma (HCC), and high ZNF706 expression was associated with unfavorable survival in HCC patients. Functional experiments revealed that ZNF706 knockdown inhibited HCC progression both in vitro and in vivo. RNA sequencing (RNA-seq) and chromatin immunoprecipitation-based deep sequencing (ChIP-seq) revealed that mechanistically, ZNF706 is a crucial ferroptosis regulator and that SLC7A11 is a critical target of ZNF706. In addition, ZNF706 knockdown inhibited SLC7A11 expression, increased lipid peroxidation, and promoted ferroptosis. Further analysis revealed that ZNF706 is a novel direct target transcriptionally activated by MYC in HCC cells. Importantly, MYC depletion reduced SLC7A11-mediated redox homeostasis, and this effect was reversed by ZNF706 reexpression. Collectively, our data demonstrate that ZNF706 is a potential oncogene in liver cancer and functions as a ferroptosis regulator by modulating SLC7A11 expression, constituting a potential therapeutic target for HCC.

肝癌中染色体 8q22 拷贝数增加的致癌潜力仍有待描述。在此，我们报道 ZNF706 由映射到染色体 8q22 的基因编码，是一种 C2H2 型锌指蛋白。然而，ZNF706的生物学功能和机制尚不清楚。临床上，ZNF706在肝细胞癌（HCC）中表达升高，并且ZNF706高表达与HCC患者的不利生存相关。功能实验表明，ZNF706 敲除可在体外和体内抑制 HCC 进展。 RNA 测序 (RNA-seq) 和基于染色质免疫沉淀的深度测序 (ChIP-seq) 揭示，从机制上讲，ZNF706 是重要的铁死亡调节因子，而 SLC7A11 是 ZNF706 的关键靶点。此外，ZNF706 敲低会抑制 SLC7A11 表达，增加脂质过氧化，并促进铁死亡。进一步分析表明，ZNF706是HCC细胞中MYC转录激活的新型直接靶点。重要的是，MYC 耗竭降低了 SLC7A11 介导的氧化还原稳态，而这种效应可通过 ZNF706 重新表达而逆转。总的来说，我们的数据表明 ZNF706 是肝癌中的潜在癌基因，并通过调节 SLC7A11 的表达作为铁死亡调节剂，构成 HCC 的潜在治疗靶点。