Dicoumaral 使肝细胞癌细胞对咪唑酮 erastin 诱导的铁死亡敏感

铁死亡是一种铁依赖性调节细胞死亡形式，其特征是脂质过氧化物在细胞膜上的致命积累。它不仅抑制肿瘤生长，还增强免疫治疗反应并克服癌症治疗中的耐药性。这 胱氨酸-谷氨酸逆向转运蛋白系统 Xc 的 i 抑制诱导铁死亡。咪唑酮 erastin （IKE） 是 的 系统 Xc 功能亚基溶质载体家族 7 成员 11 （SLC7A11） 的抑制剂，是一种有效且代谢稳定的铁死亡诱导剂，具有潜在的体内应用。然而，肿瘤细胞 对IKE 诱导的铁死亡表现出不同的敏感性。决定对 IKE 诱导的铁死亡敏感性的内在因素仍有待探索以提高其疗效。从癌症基因组图谱 （TCGA） 和基因型组织表达 （GTEx） 数据库中收集来自肝细胞癌 （HCC） 和正常肝组织的大量 RNA 测序数据。鉴定差异表达基因并与 FerrDb 数据库中列出的铁死亡相关基因 （FRG） 相交，鉴定 13 个不同的 FRG。开发了铁死亡特征指数模型 （Risk Score） 来预测 HCC 预后。SLC7A11 和 NAD（P）H 醌脱氢酶 1 （NQO1） 被确定为候选 FRGs，表明预后之。NQO1 抑制剂 Dicoumarol （DIC） 随后被用于评估其在 HCC 治疗中 。在 HCC 细胞系和皮下异种移植模型中，SLC7A11和 NQO1 的联合抑制通过诱导铁死亡显着增强了对肿瘤生长的抑制作用。总之，我们的研究结果表明，DIC 使d HCC 细胞对 IKE 诱导的 铁死亡HCC。此外，鉴定增强 HCC 细胞对铁死亡易感性的潜在药物可为 HCC 的治疗提供新的治疗策略。

Ferroptosis is an iron-dependent form of regulated cell death characterized by the lethal accumulation of lipid peroxides on cell membranes. It not only suppresses tumor growth, but also enhances immunotherapeutic responses and overcomes drug resistance in cancer therapy. Inhibition of the cystine-glutamate antiporter system Xc- induces ferroptosis. Imidazole ketone erastin (IKE), an inhibitor of solute carrier family 7 member 11 (SLC7A11), the functional subunit of system Xc-, is a potent and metabolically stable ferroptosis inducer with potential in vivo applications. However, tumor cells exhibit diverse sensitivities to IKE-induced ferroptosis. The intrinsic factors determining the sensitivity to IKE-induced ferroptosis remain to be explored to improve its therapeutic efficacy. Large-scale RNA sequencing data of hepatocellular carcinoma (HCC) and normal liver tissues were collected from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Differentially expressed genes (DEGs) were identified and intersected with ferroptosis-related genes (FRGs) listed in the FerrDb database, yielding 13 distinct FRGs. A ferroptosis signature risk score model was developed to predict the prognosis of HCC. SLC7A11 and NAD(P)H quinone dehydrogenase 1 (NQO1) were identified as candidate FRGs. The NQO1 inhibitor Dicoumarol (DIC) was subsequently used to evaluate its role in HCC treatment. In HCC cell lines and subcutaneous xenograft models, combined inhibition of SLC7A11 and NQO1 significantly enhanced the suppression of tumor growth by inducing ferroptosis. Collectively, our results indicate that DIC sensitizes HCC cells to IKE-induced ferroptosis. Furthermore, identification of potential drugs that enhance the susceptibility of HCC cells to ferroptosis can provide novel therapeutic strategies for HCC treatment.