Synergistic Anti-Inflammatory Effects of Pomegranate Peel-Hawthorn Combinations in Ulcerative Colitis: Network Pharmacology Prediction and Experimental Validation.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by complex pathogenesis involving dysregulated immunity and gut microbiota imbalance, demanding innovative therapeutic strategies. This study investigates the synergistic therapeutic potential of pomegranate peel-hawthorn combinations and their active constituents (ellagic acid and maslinic acid) through an integrative approach combining network pharmacology, in vitro/in vivo experiments, and gut microbiota analysis. Network pharmacology identified 61 shared therapeutic targets (p < 0.05 for pathway enrichment) and revealed complementary mechanisms: pomegranate peel primarily modulated AGE-RAGE/PI3K-Akt pathways, while hawthorn targeted IL-17/NF-κB signaling. Experimental validation demonstrated potent synergistic anti-inflammatory effects (combination index < 1), with optimal combinations reducing nitric oxide production by 52.35% (herbal extracts, p < 0.05) and 74.4% (active monomers, p < 0.05). In DSS-induced UC mice, combinatorial therapies significantly suppressed pro-inflammatory cytokines (TNF-α: 204.78 vs. 446.52 pg/mL in UC group, p < 0.05; IL-6: 33.19 vs. 64.86 pg/mL, p < 0.05), restored colonic SOD activity (72.31 vs. 50.10 U/mg·prot in UC group, p < 0.01), and alleviated histopathological damage, outperforming monotherapeutics. Gut microbiota analysis revealed the recovery of α-diversity indices and normalized Bacteroidota/Bacillota ratios. Mechanistically, the combinations suppressed MAPK/NF-κB signaling cascades, reducing p-p38/p38 (p < 0.01 vs. UC group) and p-ERK1/2/ERK1/2 (p < 0.01 vs. UC group) phosphorylation. These findings establish that pomegranate peel-hawthorn formulations exert multi-modal therapeutic effects through the synergistic inhibition of pathways, mitigation of oxidative stress, and restoration of the microbiota, offering a scientifically validated approach for UC management rooted in traditional medicine principles.