Abstract
ObjectiveThis study aimed to identify the mechanism of Yiqi Huayu Decoction (YQHY) induced ferroptosis in gastric cancer (GC) by using network pharmacology and experimental validation.MethodsThe targets of YQHY, ferroptosis-related targets, and targets related to GC were derived from databases. Following the protein–protein interaction (PPI) network, the hub targets for YQHY induced ferroptosis in GC were identified. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were used to analyze the hub targets from a macro perspective. We verified the hub targets by molecular docking, GEPIA, HPA, and the cBioPortal database. Finally, we performed cell viability assays, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, lipid peroxidation, and GSH assays to explore the mechanism of YQHY induced ferroptosis in GC.ResultsWe identified the main active compounds and hub targets: Quercetin, DIBP, DBP, Mipax, Phaseol and TP53, ATM, SMAD4, PTGS2, and ACSL4. KEGG enrichment analyses indicated that the JAK2-STAT3 signaling pathway may be a significant pathway. Molecular docking results showed that the main active compounds had a good binding activity with the hub targets. The experimental results proved that YQHY could induce ferroptosis in AGS by increasing the MDA content and reducing the GSH content. qRT–PCR and Western blot results showed that YQHY can induce ferroptosis in GC by affecting the JAK2-STAT3 pathway and the expression of ACSL4.ConclusionsThis study indicated that YQHY can induce ferroptosis in GC by affecting the JAK2–STAT3 pathway and the expression of ACSL4, and induction of ferroptosis may be one of the possible mechanisms of YQHY’s anti-recurrence and metastasis of GC.
Highlights
The incidence of gastric cancer (GC) in China accounts for nearly half of the world [1, 2]
3.1.3 Screening of Hub Targets for Yiqi Huayu Decoction (YQHY) Induced Ferroptosis in GC According to the ranking of BC, Cellular Component (CC), and degree calculated by the CytoNCA plug-in, TP53, ATM, SMAD4, PTGS2, and ACSL4 were identified as the hub targets of YQHY induced ferroptosis in GC
Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis showed that the hub targets were mainly enriched in microRNAs in cancer and the JAK2-STAT3 signaling pathway (Figure 4), suggesting that the JAK2-STAT3 pathway is one of the main potential signaling pathways of YQHY induced ferroptosis in GC
Summary
The incidence of GC in China accounts for nearly half of the world [1, 2]. Surgery is considered the only radical cure method [3]. GC has a high cure rate, whereas advanced GC is characterized by a high metastasis rate, a high mortality rate, a low curative resection rate, and a poor five-year survival rate [4]. The occurrence and development of cancer are closely related to cell death. One of the important characteristics of cancer cells is avoiding death. It is necessary to explore a new strategy to treat GC by inducing tumor cell death
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