Targeting Fatty Acid Synthase With Berberine Promotes IL ‐10 Production in Macrophages and Prevents Relapse in a Murine Colitis Model

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by alternating periods of remission and relapse. Current therapeutic options for maintaining long-term remission are limited, and no established animal model exists for evaluating relapse. We hypothesized that enhancing interleukin-10 (IL-10) production in intestinal macrophages could serve as a novel therapeutic strategy. Through the screening of a library of natural compounds derived from medicinal herbs, we identified berberine as a promising IL-10 enhancer. This study aimed to develop an experimental relapse model and elucidate the mechanism through which berberine promotes IL-10 production. Male C57BL/6 mice were subjected to two cycles of dextran sulfate sodium (DSS) treatment to induce colitis relapse. Bone marrow-derived macrophages (BMDMs) were treated with berberine before LPS stimulation, and IL-10 levels were measured. Drug affinity responsive target stability (DARTS) analysis was used to identify berberine-binding proteins. Berberine increased IL-10 expression in the colons of treated mice and suppressed colitis relapse when it was administered during the recovery phase. Additionally, berberine promoted colonic mucosal wound repair in vivo. In vitro, berberine enhanced LPS-induced IL-10 secretion by BMDMs. DARTS analysis revealed fatty acid synthase (FASN) as a direct berberine-binding protein. The FASN inhibitor cerulenin and Fasn knockdown both attenuated berberine-induced IL-10 production, suggesting a FASN-dependent augmentation pathway. These findings indicate that berberine suppresses colitis relapse by enhancing IL-10 production in macrophages via FASN binding. Our study highlights the increase in IL-10 levels through FASN as a promising strategy for maintaining remission in patients with IBD.