https://orcid.org/0009-0000-9058-9389
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Abstract
Background
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.
Purpose
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.
Methods
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.
Results
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.
Conclusion
Celastrol induces ferroptosis in HCC via regulating GSTM1 expression and may serve as a novel therapeutic compound with clinical potential in HCC treatment.
Graphical Abstract
Abbreviations
HSCs, hepatic stellate cell; HCC, hepatocellular carcinoma; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; GSTM1, Glutathione S-transferase Mu 1; ROS, reactive oxygen species; MDA, malondialdehyde; GSH-Px, glutathione peroxidase, GPX4, glutathione peroxidase 4; COMMD10, Copper metabolism MURR1 domain 10; HIF1α, Hypoxia-inducible factor 1-alpha; CP, ceruloplasmin; LCN2, Neutrophil gelatinase-associated lipocalin; GLS2, Glutamine synthase 2; ccRCC, clear cell renal cell carcinoma; SDF, Structure Data File; BP, biological process; CC, cellular composition; MF, molecular function; OS, overall survival; KM, Kaplan-Meier; ROC, receiver operating characteristic; PDB, Program DataBase, MOE, Molecular Operating Environment; MEM, minimum essential Medium; FBS, fetal bovine serum; Fer-1, Ferrostatin-1; DFO, Deferoxamine mesylate; NAC, N-acetylcysteine; NADPH, nicotinamide adenine dinucleotide phosphate; GR, Glutathione Reductase; Edu, 5-ethynyl-2’-deoxyuridine; PMSF, phenylmethylsulfonyl fluoride; GSTs, Glutathione S-transferases; Nrf2, nuclear factor erythroid 2-related factor 2.
Data Sharing Statement
All data that support the findings of this study are included in this manuscript and its Supplementary Files. Further inquiries can be directed to the corresponding author.
Ethical Approval
All databases in this study are public databases, the contents of which are publicly available and allow unrestricted reuse through open licenses. According to an official document issued by the National Science and Technology Ethics Committee of China, the use of legally obtained public data is not subject to ethical scrutiny (https://www.gov.cn/zhengce/zhengceku/2023-02/28/content_5743658.htm). Therefore, the part of this study involving human data from public databases would need ethics approval waived (Ethics Committee of Shanghai Pudong Gongli Hospital). The proof of ethical exemption has been provided in Supplementary File 2.
Acknowledgments
This work is grateful for the above funding. Thanks to Dr.Bin Peng and Dr. Yijun Tian for critically reading the manuscript. We sincerely appreciate the time and effort of all who contributed to this study.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare that there are no conflicts of interest in this work.