Ursodeoxycholic Acid Alleviates DSS/AOM-Induced Colorectal Cancer in Mice by Inhibiting PI3K/Akt/mTOR Signaling Pathway.

Introduction: Ursodeoxycholic acid (UDCA) demonstrates potential therapeutic effects against colorectal cancer (CRC) due to its anti-inflammatory and immunomodulatory properties; however, its precise molecular mechanisms remain incompletely understood. Methods: This study employed an integrative approach combining network pharmacology, molecular docking, and in vivo validation in an AOM/DSS-induced mouse model to investigate the specific molecular targets of UDCA and its associated effects on the gut microenvironment. Results: UDCA significantly alleviated colitis-associated tumorigenesis and reduced tumor burden, which was associated with the inhibition of the PI3K/Akt/mTOR signaling pathway. Molecular docking and experimental verification identified EGFR as a key upstream target directly engaged by UDCA to suppress this oncogenic axis. Furthermore, UDCA treatment improved the tumor microenvironment, characterized by suppressed pro-inflammatory cytokines, regulated metabolic gene expression (including CYP19A1 and HMGCR), and a shift toward gut microbiota homeostasis through the enrichment of beneficial taxa and short-chain fatty acids. Conclusion: These findings suggest that UDCA exerts its anti-tumor effects primarily through direct inhibition of the EGFR-mediated PI3K/Akt/mTOR pathway, accompanied by partial restoration of the intestinal immune-metabolic microenvironment. This study provides new mechanistic insights supporting the therapeutic application of UDCA in CRC.