The eicosanoid-cell death axis: A mechanistic review of crosstalk in health and disease

Eicosanoids, a diverse family of lipid mediators from arachidonic acid (AA), are fundamental regulators of inflammation and cellular signaling. Concurrently, regulated cell death (RCD) pathways—including apoptosis, necroptosis, pyroptosis, and ferroptosis—are essential, genetically encoded programs that maintain tissue homeostasis by eliminating damaged or unwanted cells. A growing body of evidence reveals that these two systems are not independent but are deeply and mechanistically intertwined, forming a critical axis that dictates cell fate. Through a systematic evaluation of current literature, this review synthesizes the multifaceted nature of this crosstalk. An analysis is presented of the molecular mechanisms by which cyclooxygenase (COX)-derived prostaglandins, such as prostaglandin E₂ (PGE₂), exert a dual influence on apoptosis, promoting survival in cancer while triggering death in immune cells. The temporal regulation of immunogenic cell death (ICD) is further explored, wherein lipoxygenase (LOX)-derived leukotrienes amplify lytic death pathways, while specialized pro-resolving mediators (SPMs) suppress them to restore homeostasis. A central focus is the paradigm-shifting discovery of LOX enzymes as direct executioners of ferroptosis, an iron-dependent form of RCD driven by catastrophic lipid peroxidation. Crucially, this review expands upon previously overlooked intracellular mediators, explicitly detailing how eicosanoid-driven oxidative stress and mitochondrial dysfunction act as fundamental convergence points for RCD modulation. Furthermore, emerging RCD modalities such as PANoptosis and cuproptosis are discussed to highlight the expanding landscape of this crosstalk. Dysregulation of this eicosanoid-RCD axis is a key driver in pathologies ranging from cancer and chronic autoimmunity to neurodegenerative diseases and cardiovascular disorders. By systematizing these molecular touchpoints, this review highlights emerging therapeutic strategies aimed at precisely targeting this nexus to restore homeostasis and treat human disease.