Network pharmacology and molecular docking technology for exploring the effect and mechanism of high-dose vitamin c on ferroptosis of tumor cells: A review

Abstract

To investigate the mechanism by which high-dose vitamin C (HVC) promotes ferroptosis in tumor cells via network pharmacology, vitamin C-related and ferroptosis-related targets were obtained from the PharmMapper and GeneCards databases, respectively, and their common targets were compared using the Venn diagram. Common targets were imported into the STRING database for protein-protein interaction analysis, and core targets were defined. Core targets were enriched for Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways using the R language packages. A map of the core target-based interaction network and a map of the mechanism by which HVC regulates ferroptosis were constructed. A total of 238 vitamin C-related and 721 ferroptosis-related targets were identified, of which 21 targets were common to both. Furthermore, ALDOA, AHCY, LDHB, HSPA8, LGALS3, and GSTP1 were identified as core targets. GO enrichment analysis suggested that the main biological processes included the extrinsic apoptotic signaling pathway and pyruvate metabolic process. KEGG enrichment analysis suggested that HVC regulates ferroptosis mainly through the amino acid and carbohydrate metabolic pathways. The targets were validated by molecular docking. In conclusion, HVC may promote ferroptosis in tumor cells by regulating metabolic pathways, and there is a synergistic effect between HVC and type I ferroptosis inducers. Glycolysis-dependent tumors may be beneficial for HVC therapy. Our study provides a reference for further clinical studies on HVC antitumor therapy.

Figure 1.

A schematic diagram of network pharmacology approach for the identification of core targets, PPI network, biological processes and key pathways in the regulation of ferroptosis by Vc. All known Vc- and ferroptosis-related targets were predicted from online databases. Then, potential targets for the regulation of ferroptosis by Vc were identified. After constructing the PPI network and identifying the core targets of Vc action on ferroptosis, GO term and KEGG pathway enrichment analyses were performed. In addition, maps of the Vc-Target-GO-KEGG-Ferroptosis network and the metabolic pathways of HVC-regulated ferroptosis were generated. Finally, the core targets were validated by molecular docking techniques. GO = gene ontology, HVC = high-dose vitamin C, KEGG = Kyoto Encyclopedia of Genes and Genomes, PPI = protein-protein interaction, Vc = vitamin C.

Figure 2.

(A) As shown in the Venn diagram (left), all targets of Vc and ferroptosis were identified. In a PPI network (right), the merged targets of Vc and ferroptosis were interacted. (B) The core targets of Vc-regulated ferroptosis were interacted and visualized in a PPI network. PPI = protein-protein interaction, Vc = vitamin C.

Figure 3.

GO analysis (A) and KEGG analysis (B) of the core targets of Vc-regulated ferroptosis. All potential GO terms and KEGG pathways were detected and optimized, and the top-ranked molecular processes were highlighted in bubble diagrams. GO = gene ontology, KEGG = Kyoto Encyclopedia of Genes and Genomes, Vc = vitamin C.

Figure 4.

Interaction network based on the core targets of Vc-regulated ferroptosis. This diagram comprehensively reveals the interaction of targets, functions and pathways of the activities of Vc in regulating ferroptosis. Vc = vitamin C.

Figure 5.

Metabolic pathway diagram of ferroptosis regulated by HVC. The potential mechanisms of HVC to regulate ferroptosis are the following three metabolic pathways: (A) targeting transsulfuration pathway to limit the supplemental synthesis of GSH; (B) targeting glycolysis to rewire glucose metabolism to the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation (OXPHOS) to increase ROS production; and (C) targeting the reaction of GSH with organic halides to increase GSH catabolism utilization. In addition, HVC may exert antitumor effects by targeting ALDOA to limit the high utilization of glucose by tumor cells. Cys = cysteine, DHAP = dihydroxyacetone phosphate, F-1,6-BP = fructose-1,6-bisphosphate, Glu = glutamate, GLUTs = glucose transporters, GSH = reduced glutathione, Hcy = L-homocysteine, Met = methionine, PGAL = glyceraldehyde 3-phosphate, R-S-CysGly = R-S-cysteinylglycine, R-S-GSH = R-S-glutathione, RX = organic halide, SAH = S-adenosyl-L-homocysteine, SAM = S-adenosyl methionine, SLC7A11 = solute carrier family 7 member 11.

Figure 6.

The molecular docking findings of Vc-regulated Ferroptosis. The core proteins of AHCY (PDB: 5W49), ALDOA (PDB: 5KY6), GSTP1 (PDB: 3GUS) and LDHB (PDB: 7DBJ) were identified to docking with Vc compound structurally. Vc = vitamin C.