Revealing the Action Mechanism of Exogenous Hydrogen Sulfide Intervention in Colorectal Cancer Pathogenesis Based on Multiomics Analysis and Experimental Validation.

Colorectal cancer (CRC) ranks among the leading causes of cancer-related mortality worldwide. Hydrogen sulfide (H2S) has been found to possess a characteristic of anticancer, which may offer a potential novel treatment for CRC. Here, we discover the potential targets and mechanism of H2S intervention in CRC employing multiomics analysis and experimental validation. The key targets of H2S intervention in CRC were identified by integrating differentially expressed genes (DEGs) from tumor and normal tissues, the CRC-associated genes, and the targets of H2S. The STRING and Cytoscape tools were explored to obtain hub genes. Functional enrichment analysis, assessment of diagnostic and prognostic significance, single-cell datasets, and cell experiments were used to explore the impact of core targets on CRC and the potential mechanism through which H2S exerts regulatory effects on CRC. Our results identified 9250 genes closely linked to CRC from DEGs and CRC-associated genes, 505 targets for H2S, and 322 potential targets of H2S intervention in CRC. Subsequently, five hub genes were filtered, including MAPK1, MAPK3, JUN, ESR1, and AKT1. The 322 common targets were enriched in the cellular stress responses and IL-17 signaling pathway. Additionally, MAPK3 had good diagnostic and prognostic value for CRC. JUN was highly expressed in immune cells. Cell experiments showed that sodium hydrosulfide (NaHS), a donor of H2S, prominently inhibited cell proliferation, promoted cell apoptosis for CRC, and downregulated the expression of MAPK1, MAPK3, AKT1, and JUN. Taken together, this study elucidates the possible genes and therapeutic mechanisms underlying exogenous H2S intervention in CRC, thereby laying a foundation for the further development of H2S-based therapeutic strategies in CRC management.