A novel triazole derivative ameliorates ulcerative colitis by targeting PPAR gamma.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that remains incurable. Although current medications can alleviate symptoms, treatment still faces major challenges such as side effects and drug resistance. Therefore, the development of new drugs is urgently needed. This study introduces a novel 1,2,3-triazole derivative, 5-phenyl-1-(p-tolyl)-1H-1,2,3-triazole (PPTT), which alleviates UC symptoms by targeting peroxisome proliferator-activated receptor gamma (PPARG) to regulate macrophage polarization and fatty acid metabolism. In a dextran sulfate sodium-induced UC mouse model, PPTT significantly improved disease symptoms. Through machine learning and multi-omics analyses, we identified PPARG as a potential therapeutic target and found that PPTT activates the PPAR and PI3K/Akt signaling pathways and regulates unsaturated fatty acid metabolism. Molecular docking, molecular dynamics simulations, surface plasmon resonance, cellular thermal shift assays, and drug affinity responsive target stability experiments confirmed the interaction between PPTT and PPARG. RT-qPCR and Western blotting further verified mRNA and protein expression levels. Inflammatory cytokine levels were analyzed using ELISA. This study indicated that PPTT exerts therapeutic effects against UC by targeting PPARG to suppress the PPAR and PI3K/Akt signaling pathways, thereby promoting the polarization of M1 macrophages toward the M2 phenotype. These findings suggest that PPTT is a promising candidate for UC treatment.