Significance: The oxidation of arachidonic acid via cyclooxygenase (COX) and lipoxygenase (LOX) activity to produce eicosanoids during inflammation is a well-known biosynthetic pathway. These lipid mediators are involved in fever, pain, and thrombosis and are produced from multiple cells as well as cell/cell interactions, for example, immune cells and epithelial/endothelial cells. Metabolic disorders, including hyperlipidemia, hypertension, and diabetes, are linked with chronic low-grade inflammation, impacting the immune system and promoting a variety of chronic diseases.

Recent Advances: Multiple studies have corroborated the important function of eicosanoids and their receptors in (non)-inflammatory cells in immunometabolic disorders (e.g., insulin resistance, obesity, and cardiovascular and nonalcoholic fatty liver diseases). In this context, LOX and COX products are involved in both pro- and anti-inflammatory responses. In addition, recent work has elucidated the potent function of specialized proresolving mediators (i.e., lipoxins and resolvins) in resolving inflammation, protecting organs, and stimulating tissue repair and remodeling.

Critical Issues: Inhibiting/stimulating selected eicosanoid pathways may result in anti-inflammatory and proresolution responses leading to multiple beneficial effects, including the abrogation of reactive oxygen species production, increased speed of resolution, and overall improvement of diseases related to immunometabolic perturbations.

Future Directions: Despite many achievements, it is crucial to understand the molecular and cellular mechanisms underlying immunological/metabolic cross talk to offer substantial therapeutic promise. Antioxid. Redox Signal. 29, 275–296.