Lipid-Driven Intrinsic Neuronal Repair After Stroke: The PLA2G2E–DGLA–PADI4 Axis

Abstract Neural repair after ischemic stroke primarily depends on the brain’s intrinsic capacities, especially in the peri-infarct region. Despite advances in understanding injury mechanisms, knowledge of the molecular processes guiding spontaneous neuronal regeneration remains incomplete. This review article examines evidence related to the PLA2G2E–DGLA–PADI4 signaling axis as an integrated molecular circuit in neural repair after stroke. The aim is to analyze the role of this axis in linking lipid metabolism with epigenetic reprogramming and structural neuronal regeneration. Results show that following ischemia in murine models, the expression of the enzyme PLA2G2E specifically increases in neurons of the penumbra area. This enzyme hydrolyzes membrane phospholipids, releasing the fatty acid DGLA. DGLA and its metabolite 15-HETrE, while modulating inflammation, activate the nuclear enzyme PADI4. PADI4, through citrullination of histone H3, opens chromatin structure and relieves epigenetic repression of genes involved in neuronal regeneration, including BDNF and GAP-43. These events lead to neurite outgrowth, synaptic reconstruction, and improved neural function. The PLA2G2E–DGLA–PADI4 axis is proposed as a promising autonomous repair mechanism in the brain that may enable neural regeneration after stroke by linking lipid signaling to stable epigenetic changes. Targeting this pathway offers a new conceptual perspective for future therapeutic interventions aimed at enhancing the brain’s intrinsic repair. Graphical Abstract Following ischemic stroke, PLA2G2E is upregulated in penumbral neurons, releasing DGLA to activate PADI4. PADI4-mediated histone citrullination relieves epigenetic repression of regeneration-associated genes (BDNF, GAP-43), promoting neurite outgrowth and synaptic reconstruction. This lipid–epigenetic axis represents an intrinsic neuronal repair mechanism after stroke