Suramin directly targets PI3K to alleviate experimental colitis by restoring intestinal barrier and activating autophagy.

Abstract

Ulcerative colitis (UC) is a chronic inflammatory gastrointestinal disorder marked by a compromised intestinal epithelial barrier and deficient autophagic activity. Suramin, a known antiparasitic medication, exhibits diverse anti-inflammatory properties, though its specific molecular targets and therapeutic efficacy in UC are not well-defined. This study evaluated suramin's protective effects in a DSS-induced acute murine colitis model and identified the underlying molecular pathways. Suramin treatment attenuated clinical symptoms, colon shortening, and mucosal inflammation in a dose-related manner. These positive outcomes included the restoration of intestinal epithelial barrier integrity, demonstrated by increased expression of tight junction proteins (ZO-1, Occludin, and Claudin-1), and enhanced autophagic flux in colonic tissues. Phosphoinositide 3-kinase (PI3K) was identified as a potential direct target of suramin through protein-protein interaction network analysis and molecular docking simulation. A biotin-suramin pull-down assay demonstrated that suramin directly interacts with the p85α regulatory subunit of PI3K, resulting in the inhibition of the overactivated PI3K/AKT/mTOR signaling pathway. Importantly, pharmacological reactivation of PI3K with its specific agonist 740 Y-P abolished the protective effects of suramin, causing intensified intestinal inflammation and barrier failure. Taken together, our results indicate that suramin protects against experimental colitis mainly by directly engaging PI3K p85α, thereby restraining the PI3K/AKT/mTOR axis to stimulate autophagy and reinforce intestinal epithelial barrier integrity. This research identifies suramin as a potential drug repurposing candidate for treating UC.