Excessive ultra-processed foods exposure aggravates ulcerative colitis via macrophage ferroptosis

Abstract

Ulcerative colitis (UC), a chronic inflammatory disease with global prevalence, is increasingly associated with environmental exposure to modern dietary hazards, particularly ultra-processed foods containing oxidized phytosterols. While industrial food processing techniques and repeated oil reuse are known to amplify formation of phytosterol oxidation products, their biological impacts on intestinal inflammation remain unexplored. This study focuses on 7-ketositosterol (KS), the most abundant phytosterol oxide found in ultra-processed foods, and its role in UC. Clinically, dietary analysis revealed a positive correlation between KS intake and Mayo score in UC patients (p < 0.05). Furthermore, in a C57BL/6 mouse model, KS was demonstrated to exacerbate dextran sulfate sodium (DSS)-induced colitis (p < 0.001). Mechanistically, KS impedes nuclear translocation of the N⁶-methyladenosine (m⁶A) demethylase AlkB homolog 5 (ALKBH5) (p < 0.05). This suppression downregulates expression of the glutamate-cysteine ligase modifier subunit (GCLM), impairing glutathione biosynthesis and ultimately triggering macrophage ferroptosis, as evidenced by increased levels of malondialdehyde (MDA), Fe²⁺, and reactive oxygen species (ROS) with statistical significance (p < 0.05). Crucially, ALKBH5 overexpression restored GCLM-mediated antioxidant defenses and mitigated ferroptosis in RAW264.7 cells (p < 0.05). Immunofluorescence confirmed KS-mediated suppression of the ALKBH5-GCLM axis in clinical specimens, exhibiting strong correlation with UC (p < 0.05). Our findings establish processed ultra-food-derived KS as a novel environmental driver of UC pathogenesis through regulation of macrophage ferroptosis. These results identify the KS-ALKBH5-GCLM-ferroptosis axis as a promising therapeutic target for UC intervention.