The crossroads of inflammation and oxidative stress: A review of the interplay between eicosanoids and reactive oxygen species

The interplay between eicosanoids and reactive oxygen species (ROS) constitutes a bidirectional, self-amplifying "master switch" that drives pathophysiology ranging from inflammation to cell death. This review elucidates the molecular architecture of this axis, detailing how ROS activates the gatekeeper enzyme cytosolic phospholipase A₂α (cPLA₂α) to release arachidonic acid (AA), while downstream enzymes (COX, LOX, CYP450) inherently generate ROS as catalytic by-products. This review specifically examines the role of this axis as the central executioner of ferroptosis, where 15-LOX-mediated peroxidation of phosphatidylethanolamine (PE) serves as the lethal signal in cancer and acute kidney injury (AKI). Pathophysiologically, it explores how this crosstalk drives immunosuppression in the tumor microenvironment (TME) via prostaglandin E₂ (PGE₂), promotes vasoconstriction in hypertension through 20-hydroxyeicosatetraenoic acid (20-HETE), and accelerates neurodegeneration via oxidative lipid modification. Crucially, this review highlights a therapeutic paradigm shift from blunt non-steroidal anti-inflammatory drug (NSAID) inhibition to precision modulation. Emerging strategies discussed include: (1) Precision Enzymatic Targeting of downstream synthases (e.g., microsomal prostaglandin E synthase-2 [mPGES-2] inhibitors) and substrate regulators (e.g., monoacylglycerol lipase [MAGL] inhibitors); (2) ROS-Responsive Nanomedicines that utilize oxidative stress to trigger drug release; and (3) Resolution Pharmacology, which utilizes precursors like omega-3 polyunsaturated fatty acids (PUFAs) to induce a lipid mediator class switch, actively terminating inflammation rather than merely suppressing it. This synthesis provides a roadmap for targeting the lipid-redox nexus to restore homeostatic balance.