Selenium-GPX4 axis orchestrates intestinal arachidonic acid metabolic reprogramming to mitigate inflammation

Dietary westernization exacerbates polyunsaturated fatty acid-mediated intestinal inflammation, though the mechanistic links between arachidonic acid (AA)-induced gut metabolic dysregulation and glutathione peroxidase 4 (GPX4)-regulated inflammatory modulation ‌require further elucidation. Employing both lipopolysaccharide (LPS)-induced and dietary AA-fed murine models, we revealed profound alterations in oxylipin profiles and catalytic enzyme expression, which were effectively alleviated by selenium (Se) supplementation via GPX4 upregulation. The LPS model was used to identify inflammation-associated alterations in AA metabolism, while the chronic dietary AA model was applied to further evaluate the pathological role of sustained AA metabolic activation in intestinal injury. Genetic approaches (Gpx4^+/-IEC and Gpx4^+/-Mye) identified intestinal epithelial cells GPX4 as the central regulator orchestrating AA metabolic flux and inflammatory cascades. Single-cell RNA sequencing analysis demonstrated that while AA exposure alone induced moderate enterocyte reduction, concomitant IEC-Gpx4 knockdown markedly potentiated this depletion. Notably, ferrostatin-1 administration alleviated oxylipin dysregulation and inflammatory activation triggered by dietary AA treatment combined with IEC-Gpx4 knockout. IEC-macrophage co-culture experiments demonstrated that IEC-Gpx4 not only corrects AA-induced oxylipin disturbances but also suppresses chemokine/cytokine release and prevents Slamf7⁺ pro-inflammatory macrophage polarization. Collectively, these findings establish the Se-GPX4-oxylipin axis as a fundamental regulatory circuit in intestinal inflammation, providing mechanistically grounded therapeutic strategies for inflammatory bowel diseases.