Regulating arachidonic acid metabolism: a novel strategy to prevent colorectal inflammatory cancer transformation.

Colorectal cancer (CRC) ranks among the leading causes of cancer-related morbidity and mortality worldwide, with colitis-associated colorectal cancer (CAC) driven by inflammatory cancer transformation. Arachidonic acid (AA), a key ω-6 polyunsaturated fatty acid, and its metabolites, including prostaglandins (PGs) and leukotrienes (LTs), play pivotal roles in this process by modulating inflammation, immune responses, and the intestinal microenvironment. Notably, a multi-enzyme co-expression nanoplatform integrating lipoxygenase (LOX) and phospholipase A (PLA) has been developed, synergistically inducing immunogenic ferroptosis and upregulating AA expression to enhance CD8 T cell-mediated anti-tumor immunity. Additionally, dual COX-2/soluble epoxide hydrolase (sEH) inhibitors, such as PTUPB, demonstrate enhanced anti-tumor activity and reduced toxicity when combined with cisplatin, offering a promising approach to mitigate gastrointestinal side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Furthermore, natural products like ginsenoside Rk3 and berberine have been identified to regulate AA metabolism and gut microbiota, alleviating CAC by modulating lipid peroxidation and inflammatory pathways. This review synthesizes these innovative findings, highlighting the role of AA metabolism in maintaining intestinal homeostasis, promoting inflammatory cancer transformation, and serving as a therapeutic target to inhibit CAC progression, thus providing new insights into its prevention and treatment.