Research progress of polyunsaturated fatty acids in inflammatory bowel disease: from mechanisms to treatment

Inflammatory bowel disease (IBD) imposes a growing clinical burden through recurrent intestinal inflammation, malnutrition, treatment-related toxicity, and incomplete mucosal healing. Polyunsaturated fatty acids (PUFAs) are plausible dietary regulators of this burden, yet their effects cannot be reduced to a simple anti-inflammatory role for n-3 PUFAs and a pro-inflammatory role for n-6 PUFAs. The proposed pre-clinical concept of PUFA-induced metabolic enteritis links dietary lipid exposure to epithelial stress, lipid peroxidation, and intestinal inflammation in genetically or metabolically susceptible pre-clinical models. Its human counterpart, however, remains incompletely defined. This narrative review integrates evidence across PUFA-derived lipid mediators, the gut microbiota, intestinal barrier function, mucosal immunity, and the glutathione peroxidase 4 (GPX4)-ferroptosis axis. We distinguish observational associations from interventional evidence and examine why clinical trials of eicosapentaenoic acid and docosahexaenoic acid have produced inconsistent results. We also evaluate dietary patterns, PUFA supplements, microbiome-directed approaches, specialized pro-resolving mediators, oxylipin pathways, and soluble epoxide hydrolase inhibition. Current evidence remains pre-clinical. Our review provides an approach and insights for managing IBD before PUFA-directed interventions are incorporated into precision treatment for IBD.