Schisandrin B identified by CMC ameliorates PGN-induced immune colitis and DSS-triggered ulcerative colitis by targeting TLR2 and blocking TLR2 heterodimerization

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition resulting from complex interactions. With current clinical treatments showing limited efficacy, IBD poses an increasing global health challenge. Analysis of the GEO database, clinical samples from IBD patients, and a dextran sulfate sodium (DSS)-induced murine colitis model consistently reveal elevated Toll-like receptor 2 (TLR2) expression at both transcriptional and protein levels, implicating it in IBD pathogenesis and highlighting its potential as a therapeutic target. Previous studies have shown that Schisandrin B (SchB) protects DSS-induced colitis, but whether it directly targets an upstream immune receptor such as TLR2, and what additional mechanisms beyond its known anti-inflammatory actions exist, remain to be explored. In this study, SchB is identified as a moderate TLR2 ligand using cell membrane chromatography (CMC). By directly binding to TLR2 and inhibiting its heterodimerization with Toll-like receptor 1 (TLR1) or Toll-like receptor 6 (TLR6), SchB exerts significant anti-inflammatory and therapeutic effects in inflammatory cell models and ameliorates both DSS-induced ulcerative colitis and peptidoglycan (PGN)-induced immune colitis in mice. SchB inhibits TLR2 signaling and activates the sequestosome 1 (p62/SQSTM1)/Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) axis, concurrently exerting anti-inflammatory, antioxidant, and anti-apoptotic effects and reinforcing intestinal barrier integrity. These findings provide new evidence of molecular mechanisms supporting SchB as a promising therapeutic candidate for IBD.