School of Basic Medicine, Ningxia Medical University, Yinchuan, People's Republic of China.
Shanghai Health Commission Key Laboratory of Artificial Intelligence (AI)-Based Management of Inflammation and Chronic Diseases, Shanghai Pudong Gongli Hospital, Shanghai, People's Republic of China.
Drug Des Devel Ther. 2024 Jul 22;18:3121-3141. doi: 10.2147/DDDT.S450324. eCollection 2024.
As a traditional Chinese medicine monomer derived from Tripterygium wilfordii Hook.f. with potential anticancer activity, celastrol can induce ferroptosis in hepatic stellate cells and inhibit their activation to alleviate liver fibrosis. Activation of ferroptosis can effectively inhibit Hepatocellular carcinoma (HCC). Whether celastrol inhibits HCC by inducing ferroptosis remains to be studied.
To explore the potential targets of celastrol against HCC through ferroptosis based on network pharmacology and to verify the anticancer effect of celastrol on HepG2 cells.
We collected celastrol targets, HCC, and ferroptosis-related genes through online databases, and got their intersection targets. Subsequently, we obtained a protein-protein interaction (PPI) network, and performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to gain key genes for further study. They were verified in vitro and were performed molecular docking. The changes in cell proliferation and ferroptosis characteristics of HepG2 cells after celastrol treatment were detected.
31 core target genes were screened for PPI network and enrichment analysis. The most significantly related KEGG pathway was chemical carcinogenesis-reactive oxygen species. The mRNA and protein levels of GSTM1 were significantly decreased after celastrol treatment. Molecular docking demonstrated the interaction between celastrol and GSTM1. Ferroptosis was induced and cell proliferation was inhibited by celastrol in HCC cells.
Celastrol induces ferroptosis in HCC via regulating GSTM1 expression and may serve as a novel therapeutic compound with clinical potential in HCC treatment.
雷公藤红素是从雷公藤中提取的一种具有潜在抗癌活性的中药单体，它可以诱导肝星状细胞发生铁死亡，从而抑制其活化，减轻肝纤维化。铁死亡的激活可以有效抑制肝癌（HCC）。雷公藤红素是否通过诱导铁死亡抑制 HCC 仍有待研究。
基于网络药理学探讨雷公藤红素通过铁死亡抑制 HCC 的潜在靶点，并验证雷公藤红素对 HepG2 细胞的抗癌作用。
我们通过在线数据库收集雷公藤红素靶点、HCC 和铁死亡相关基因，并获得它们的交集靶点。随后，我们构建了一个蛋白质-蛋白质相互作用（PPI）网络，并进行了基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析，以获得进一步研究的关键基因。我们在体外进行了验证，并进行了分子对接。检测了雷公藤红素处理后 HepG2 细胞增殖和铁死亡特征的变化。
从 PPI 网络和富集分析中筛选出 31 个核心靶基因。与疾病最相关的 KEGG 通路是化学致癌作用-活性氧。雷公藤红素处理后 GSTM1 的 mRNA 和蛋白水平明显降低。分子对接表明雷公藤红素与 GSTM1 相互作用。雷公藤红素在 HCC 细胞中诱导铁死亡并抑制细胞增殖。
雷公藤红素通过调节 GSTM1 的表达诱导 HCC 发生铁死亡，可能成为 HCC 治疗中具有临床潜力的新型治疗化合物。
