Deciphering the molecular mechanism of sesamol in inflammatory bowel disease through an integrative computational and biological evaluation of the JAK1 signalling pathway.

Abstract

Inflammatory bowel disease (IBD) is a major chronic inflammatory disorder whose pathogenesis involves impaired mucosal barrier function, dysbiosis, immune dysregulation, and oxidative stress. The JAK-STAT signalling axis plays a pivotal role in driving inflammatory cytokine response in IBD. Consequently, natural antioxidant and anti-inflammatory compounds have emerged as promising therapeutic candidates. This study aimed to elucidate the molecular mechanisms underlying the anti-IBD potential of sesamol through an integrative computational and experimental approach. Potential sesamol-associated targets were identified using network pharmacology and protein-protein interaction analyses. Gene Ontology and KEGG pathway enrichment were conducted to identify key biological processes and signalling pathways. Molecular docking, molecular dynamics simulations, and MM-GBSA binding free energy calculations were performed by Schrödinger V14.1.38 to evaluate interactions with Janus kinases. Therapeutic relevance was validated using dextran sulphate sodium (DSS)-induced murine colitis model. Sixty-three overlapping therapeutic targets were identified, with JAK1 and JAK2 emerging as central signalling nodes. Sesamol exhibited strong binding affinity toward both kinases, forming a more stable and sustained complex with JAK1, as evidenced by lower RMSD and RMSF values and favourable MM-GBSA energies compared with JAK2. In vivo, JAK1 expression was significantly elevated in inflamed colonic tissue and was markedly normalised following sesamol treatment, corroborating computational predictions. Sesamol exerts protective effects in IBD by modulating the JAK-STAT signalling pathway, reducing intestinal inflammation, and promoting mucosal restoration. These findings highlight sesamol as a promising multi-target natural candidate for restoring immune homeostasis and intestinal barrier integrity in IBD.