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 (<i>p</i> < 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, <i>p</i> < 0.05) and 74.4% (active monomers, <i>p</i> < 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, <i>p</i> < 0.05; IL-6: 33.19 vs. 64.86 pg/mL, <i>p</i> < 0.05), restored colonic SOD activity (72.31 vs. 50.10 U/mg·prot in UC group, <i>p</i> < 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 (<i>p</i> < 0.01 vs. UC group) and p-ERK1/2/ERK1/2 (<i>p</i> < 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.