Integrative network pharmacology and machine learning identify potential targets of indole-3-lactic acid in colorectal cancer.

Abstract

The treatment of colorectal cancer (CRC) remains challenging due to chemotherapy resistance and genetic heterogeneity. Indole-3-lactic acid (ILA), a tryptophan metabolite derived from gut microbiota, exhibits promising anti-inflammatory and anticancer properties; however, its specific molecular targets and regulatory mechanisms in CRC remain poorly understood. In this study, we combined network pharmacology and machine learning with molecular docking to identify candidate targets and pathways for ILA in CRC. We identified 39 ILA-CRC common targets, ultimately identifying four hub genes through the intersection of machine learning models. Validation in independent GEO datasets confirmed significant differential expression of these genes in CRC tissues. Functional enrichment analyses linked these genes to the PPAR, PI3K-AKT, and IL-17 signaling pathways, and gene set enrichment analysis further implicated ascorbate and aldarate metabolism, DNA replication, and fatty acid metabolism. Immune infiltration analysis indicated associations between hub gene expression and immune cell populations, including mast cells, neutrophils, and macrophages, suggesting potential involvement in the tumor immune microenvironment. Molecular docking supported favorable binding of ILA to all four hub proteins, and 100-ns molecular dynamics simulations specifically validated the dynamic stability of the ILA-HMOX1 complex. In conclusion, these results highlight EPHA2, HMOX1, MMP3, and PARP1 as candidate targets and suggest that ILA may influence CRC-related signaling, metabolic programs, and immune contexture, providing a theoretical foundation for developing gut microbiota-derived metabolites as novel anticancer strategies.