Matrine improves bile acid metabolism and reduces inflammatory and oxidative stress in inflammatory bowel disease (IBD) via suppressing JAK2 pathway

Background Inflammatory bowel disease (IBD) is a chronic inflammatory disorder often involving bile acid malabsorption. While the natural compound matrine has known anti-inflammatory properties, its therapeutic mechanism in IBD is unclear. This study aimed to elucidate matrine's potential by identifying its molecular targets and effects in IBD. Methods First, bioinformatics and molecular docking were used to identify potential drug targets. A multi-model approach was then employed, utilizing a dextran sulfate sodium (DSS)-induced IBD mouse model, a lipopolysaccharide (LPS)-stimulated MODE-K intestinal epithelial cell model, and clinical colon and serum samples from IBD patients. The effects of matrine on inflammatory cytokines, oxidative stress markers, and bile acid levels were detected using ELISA and various commercial kits. Gene and protein expression levels were assessed by qRT-PCR, immunoblotting, and immunohistochemistry. Intracellular reactive oxygen species (ROS) were measured by flow cytometry. The primary mechanism was confirmed via lentiviral-mediated JAK2 overexpression experiments. Results Bioinformatics identified JAK2 as a key hub target for matrine, and molecular docking predicted a direct binding interaction. The clinical relevance of this pathway was confirmed in human IBD patients, where JAK2 was found to be upregulated, while bile acid transporters and overall serum bile acid levels were decreased and correlated negatively with disease severity. In a DSS-induced colitis mouse model, matrine treatment ameliorated disease symptoms, reduced key inflammatory markers (IL-1β, TNF-α, IL-6) and oxidative stress indicators (including ROS), and restored bile acid homeostasis by upregulating transporters such as MRP3 and MRP4. Critically, the mechanism was confirmed to be JAK2-dependent in vitro ; experiments demonstrated that JAK2 overexpression alone was sufficient to induce pathology and that it completely reversed the therapeutic effects of matrine. Conclusion Matrine alleviates IBD by targeting the matrine-JAK2 axis, a key therapeutic pathway that was validated in human patients. This action restores bile acid metabolism and suppresses inflammation in a JAK2-dependent manner, correcting a fundamental driver of IBD pathophysiology.