Scutellarein Alleviates Ulcerative Colitis by Reshaping Gut Microbiota and Regulating the PRMT1‐Mediated Th17/Treg Balance

ABSTRACT Ulcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa with an increasing global burden and limited therapeutic efficacy. Scutellarein (Scu), a bioactive flavonoid found in various edible plants of Lamiaceae and Verbenaceae , has been shown to possess anti‐inflammatory and antioxidant activities. Herein, we systematically evaluated the effectiveness of scutellarein in the treatment of UC and identified its direct target and underlying inflammation suppression mechanism. Integrated 16S rRNA sequencing and untargeted metabolomics showed that scutellarein preserves gut microbial and metabolic homeostasis and enhances intestinal barrier integrity via enrichment of D‐(‐)‐quinic acid (DQ). Limited proteolysis mass spectrometry (Lip‐MS) identified protein arginine methyltransferase 1 (PRMT1) as a bona fide target of scutellarein. Mechanistic investigations further uncovered that scutellarein directly binds to the Y128 residue of PRMT1, which in turn inhibits STAT3 asymmetric dimethylation and phosphorylation. This cascade collectively downregulates RORγt expression, restrains Th17 differentiation, and ultimately restores the Th17/Treg cell equilibrium. Overall, scutellarein exerts dual protective effects in UC by reinforcing epithelial barrier function through microbiota‐metabolite regulation and suppressing mucosal inflammation via the PRMT1/STAT3/RORγt axis. Our findings not only elucidate a novel multicomponent mechanism for a natural product but also nominate PRMT1 as a compelling new therapeutic target for UC.