Pharmacological modulation of 5-lipoxygenase, soluble epoxide hydrolase and 15-lipoxygenase as potential therapy for inflammatory disease

The inflammatory response is a tightly regulated process activated by tissue injury or infection to restore homeostasis. It involves a complex network of pro- and anti-inflammatory signals coordinated through interactions between endothelial cells and immune cells. Lipid mediators derived from polyunsaturated fatty acids (PUFAs), particularly specialized pro-resolving mediators (SPMs), are essential for both the initiation and active resolution of inflammation. Current therapies mainly target the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways or rely on immunosuppression. While effective, these approaches are associated with significant adverse effects and limitations, whereas biologics, despite improved specificity, remain costly and immunogenic. This work emphasizes pro-resolution pharmacology, focusing on enhancing endogenous SPM biosynthesis. Approaches include omega-3 PUFA supplementation and the development of small-molecule modulators targeting soluble epoxide hydrolase (sEH) and 5-LOX. Dual inhibitors showed promising anti-inflammatory activity and structure activity relationships for inhibition of sEH and 5-LOX were elucidated. FLAP inhibitors were identified as dual-function agents that suppress leukotrienes while promoting SPM formation. Additionally, natural compounds such as cannabidiol (CBD) and magnolol were found to enhance SPM biosynthesis via modulation of 15-LOX-1, with synergistic effects observed in combination with omega-3 PUFAs. Overall, these findings support the development of multi-target, pro-resolving therapeutic strategies as effective alternatives to conventional anti-inflammatory treatments.