A santonin derivative, QX-6, alleviates ulcerative colitis by suppressing macrophage oxidative stress and inflammatory responses via modulation of ferroptosis-related signaling

Ulcerative colitis (UC) is an inflammatory bowel disease primarily affecting the colon and rectum. Current therapies, including corticosteroids, immunosuppressants, biologics, and 5-aminosalicylates, remain limited by suboptimal efficacy, adverse effects, and drug resistance, highlighting the need for safer and more effective therapeutic agents. In the present study, we identified QX-6 as a novel small-molecule compound with potent anti-inflammatory activity. In lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and bone marrow-derived macrophages (BMDMs), QX-6 markedly reduced the expression of pro-inflammatory cytokines and reactive oxygen species (ROS) production. Multi-omics analyses further revealed significant enrichment of ferroptosis related pathways following QX-6 treatment. Consistently, QX-6 regulated the expression of ferroptosis-related proteins, including NRF2, HMOX1, GCLM, GPX4, FTL, and SLC40A1, while reducing ROS accumulation and lipid peroxidation and ameliorating ferroptosis-associated mitochondrial alterations in macrophages. Moreover, pharmacological induction of ferroptosis partially reversed the inhibitory effects of QX-6 on inflammatory cytokine expression and lipid peroxidation, further supporting the involvement of ferroptosis-related signaling in its anti-inflammatory activity. In vivo, QX-6 treatment significantly alleviated colon shortening in experimental models of UC, with the 120mg/kg dose showing the strongest protective effect, surpassing that of the positive control drug 5-aminosalicylic acid. Overall, these findings demonstrate that QX-6 exerts significant anti-inflammatory effects both in vitro and in vivo, and suggest that it may serve as a promising therapeutic candidate for UC.