Multi-omics analysis reveals that FABP2 suppresses colorectal cancer progression by regulating sphingomyelin metabolism via the PPAR signaling pathway

Colorectal cancer (CRC) is a highly prevalent and lethal digestive - tract malignancy. Its global incidence and mortality are on the rise. Understanding the underlying mechanisms of CRC development is crucial for improving clinical diagnosis and treatment. The study employed Mendelian Randomization (MR) analysis, considering plasma proteins, metabolites, and tissue genes as exposure factors and CRC risk as the outcome. Key molecules were identified, and mediation MR explored their relationships. Bioinformatics analyses, using CRC Bulk RNA-Seq and scRNA-Seq data, validated the expression and functions of key molecules. Finally, the expression and regulatory mechanisms of the identified proteins and metabolites were validated using clinical tissue specimens and cell-mouse experiments. MR analysis showed 16 plasma proteins and 87 metabolites had causal relationships with CRC. FABP2, a plasma protein, was negatively correlated with CRC risk, while sphingomyelin was positively associated. Mediation MR indicated sphingomyelin mediated FABP2’s protective effect. Bulk RNA-seq data showed that FABP2 expression was significantly lower in CRC tissues compared to normal tissues. GSEA enrichment and PPI analyses revealed that FABP2 is closely associated with lipid metabolic processes. scRNA-seq further revealed that FABP2 is primarily expressed in epithelial cells, and its expression was markedly reduced in epithelial cells from tumor tissues relative to adjacent normal tissues. Clinical validation confirmed that FABP2 expression was significantly downregulated in tumor tissues and CRC patient plasma, whereas sphingomyelin levels were significantly elevated. Finally, vitro and vivo experiments combined with RNA-Seq demonstrated that FABP2 may regulate sphingomyelin metabolism and modulate CRC progression via the PPAR signaling pathway. FABP2 and sphingomyelin are closely related to CRC development. FABP2 may inhibit CRC progression by regulating sphingomyelin metabolism through the PPAR signaling pathway, suggesting its potential as a candidate biomarker for CRC diagnosis and a potential target for therapeutic intervention.