Isobavachalcone ameliorates TNBS-induced Crohn's disease-like colitis via GPR84-PI3K-AKT axis

The traditional Chinese medicine Psoralea corylifolia L. (PCL) has been clinically used to treat diarrhea and gastrointestinal inflammatory disorders. G protein-coupled receptor 84 (GPR84) is emerging as a potential target for inflammatory bowel disease (IBD). Pharmacological investigations confirm the efficacy of PCL against IBD, but its active components targeting GPR84 and their mechanisms remain unclear.

We aimed to identify active components from PCL against GPR84, evaluate their therapeutic effects and elucidate their mechanisms of action in IBD treatment.

The GPR84 screening model was established using dynamic mass redistribution (DMR) assays, with isobavachalcone identified as an antagonist. Its activity was confirmed by fluorescence imaging plate reader and cellular thermal shift assays. The binding interactions were analyzed through DMR co-stimulation assay, molecular docking and molecular dynamics simulations. The efficacy of isobavachalcone was assessed in lipopolysaccharide-stimulated RAW264.7 macrophages and 2,4,6-trinitrobenzene sulfonic acid-induced Crohn's disease-like colitis mice model. RNA sequencing, siRNA knockdown and western blotting were used to elucidate its molecular mechanism.

Isobavachalcone was identified as a selective GPR84 antagonist. It stably bound to GPR84 via π-cation, π-π stacking and hydrogen bonding interactions. In vitro, isobavachalcone demonstrated potent anti-inflammatory activity. In vivo, isobavachalcone markedly alleviated body weight loss, colonic shortening, colonic damage and macrophage infiltration. Moreover, isobavachalcone protected intestinal barrier integrity and inhibited proinflammatory cytokines, especially macrophage-produced Tnf-α, Il-6, Il-1α/β and Il-23. Mechanistically, isobavachalcone inhibited the GPR84-PI3K-AKT axis.

This study reveals the underlying mechanisms of PCL and identifies isobavachalcone as a potential candidate for Crohn's disease treatment, providing scientific basis for its clinical efficacy.