Activation of the Nrf2/HO-1/GPX4 pathway by cGAMP Mitigates oxidative stress and ferroptosis in ischaemic stroke.

Ischemic stroke(IS), a leading cause of neurological disability worldwide, involves intricate crosstalk between oxidative stress and regulated cell death pathways. In this study, we demonstrate that the immunomodulatory metabolite 2'3'-cyclic GMP-AMP (cGAMP) exerts neuroprotective effects using a mouse model of transient focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO), significantly decreased brain lesion size with concurrent amelioration of neurobehavioral outcomes through mechanisms distinct from canonical cGAS-STING signaling. cGAMP-dependent activation of the Nrf2/HO-1/GPX4 pathway was identified by multimodal interrogation as the primary mechanism curbing mitochondrial oxidative stress and lipid peroxidation, accompanied by ultrastructural preservation of mitochondrial cristae integrity and a reduction in ferroptotic markers. Pharmacological inhibition of Nrf2 using ML-385 or GPX4 with ML-210 completely abrogated these protective effects, thereby confirming pathway specificity. These findings establish cGAMP as a novel dual modulator of redox homeostasis and ferroptosis in ischemic stroke pathophysiology.