Schisantherin A alleviates DSS-induced colitis by upregulating ferredoxin 1 to inhibit inflammation and restore intestinal barrier function.

Abstract

BACKGROUND: Ulcerative colitis (UC) is a chronic non-specific inflammatory disease of the intestine with unknown etiology, and its effective treatments are still lacking. Repairing the intestinal mucosal barrier and reducing persistent inflammation is the key strategies for the treatment of UC. Schisantherin A (Sin A), a lignan compound extracted from Schisandra chinensis, exhibits anti-inflammatory, antioxidant, and neuroprotective effects. However, the role and mechanism of Sin A in the treatment of UC remains unclear. PURPOSE: This study aims to investigate the effect of Sin A on UC and elucidate its underlying molecular mechanism. METHODS: The effect of Sin A on UC was evaluated using a 3 % dextran sulfate sodium (DSS)-induced mouse model. Transcriptome sequencing analysis was performed to preliminarily explore the mechanism of Sin A in colitis. Based on the transcriptome results, the expression of proteins and mRNAs related to the FDX1-PI3K/AKT axis was determined by qPCR, immunofluorescence (IF), and western blotting. Additionally, plasmid transfection, molecular docking, drug affinity responsive target stability (DARTS), and cellular thermal shift assay (CETSA) were employed to verify the interaction between FDX1 and Sin A. RESULTS: Sin A can alleviate the clinical symptoms of UC mice, inhibit intestinal inflammation and repair intestinal barrier damage. Both transcriptomic sequencing results and ex vivo experiments confirmed that the therapeutic effect of Sin A on UC is associated with modulation of the FDX1-PI3K/AKT axis. Further studies demonstrated that FDX1 is a critical target for Sin A to inhibit the PI3K/AKT signaling pathway and exert its anti-UC effect. CONCLUSION: This study demonstrates for the first time that Sin A is a potential natural active ingredient for the treatment of UC, as it alleviates UC by suppressing inflammation and preventing barrier disruption. Furthermore, the critical role of the FDX1-PI3K/AKT axis in UC was confirmed, providing a theoretical basis for the application of Sin A.