Abstract

Ulcerative colitis (UC), a refractory chronic inflammatory bowel disease (IBD), lacks adequate treatments, necessitating new natural therapeutic candidates. Schisandrin A (Sch A), a bioactive lignan from Schisandra chinensis, was explored for its protective efficacy against dextran sulfate sodium (DSS)-induced UC in mice. Sch A markedly repaired colonic barrier function, and remodeled gut microbiota by enriching probiotics and depleting pathogenic bacteria, as verified via 16S rRNA sequencing. Mechanistically, Sch A robustly suppressed ferroptosis in vivo and in vitro. Multiomics analyses pinpointed arachidonate 15-lipoxygenase (ALOX15) as a core target. Molecular docking (MD), dynamics simulations, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) experiments confirmed the direct binding between Sch A and ALOX15. In summary, Sch A alleviates UC via regulating gut flora and targeting ALOX15 to block ferroptosis, representing a promising food-derived agent for UC therapy.