Fagopyrum cymosum Extract Improves Mitochondrial Function and Reduces Colonic Inflammation in Ulcerative Colitis by...

Background/Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited therapeutic options. Although Fagopyrum cymosum exhibits anti-inflammatory and antioxidant activities, its efficacy in UC and the underlying mechanisms are not well defined. Here, we evaluate whether Fagopyrum cymosum extract (RFC) alleviates DSS-induced colitis in mice and investigate the involvement of the PI3K/Akt/FOXO3A pathway. Methods: C57BL/6 mice received 2% DSS for 14 days, followed by 7-day intragastric RFC (low: 234 mg/kg; medium: 468 mg/kg; high: 936 mg/kg) with 5-ASA (200 mg/kg) as a control. Disease activity index (DAI), colon length, histopathology, bacterial translocation, and organ indices were assessed. Colonic mitochondrial membrane potential (JC-1), ATP, oxidative markers (SOD, GSH-px, MDA), and cytokines (IL-6, IL-1β, TNF-α) were measured. Network pharmacology, qPCR, and Western blotting were performed, alongside a PI3K agonist (740Y-P) rescue experiment. Results: RFC dose-dependently improved weight loss, DAI, colon shortening, mucosal damage, bacterial loads, and immune organ indices. It restored mitochondrial function, reduced MDA, elevated SOD/GSH-px, and suppressed inflammatory cytokines. Mechanistically, RFC inhibited PI3K/Akt phosphorylation and upregulated FOXO3A, effects reversed by 740Y-P, which also abolished RFC's protective, antioxidant, and anti-inflammatory actions. Conclusions: RFC ameliorates DSS-induced colitis by suppressing PI3K/Akt signaling and upregulated FOXO3A expression, thereby preserving mitochondrial function, reducing oxidative stress, and alleviating colonic inflammation. The PI3K/Akt/FOXO3A axis emerges as a promising therapeutic node, and RFC merits further evaluation for UC treatment.