SerpinA3N inhibits mitochondrial complex I activity to prevent neuron ferroptosis following cerebral ischemic stroke.

SerpinA3N, a serine protease inhibitor, plays emerging roles in programmed cell death regulation, yet its intracellular function in neuronal ferroptosis remains unexplored. Using the multi-omic integrative analyses of the neurons from middle cerebral artery occlusion (MCAO) challenged mouse model, we found that Serpina3n-deficient mice exhibited significantly dysregulated ferroptosis signaling networks characterized by mitochondrial lipid peroxidation amplification and redox homeostasis collapse as compared to wide type mice. An arginine mutation at position 90 of Ndufs3, the catalytic core subunit of mitochondrial complex I, in HT-22 cells impaired the binding of Ndufs3 with SerpinA3N and potentiated ferroptosis of HT-22 cells following oxygen glucose deprivation/reperfusion (OGD/R). Furthermore, neuron-specific Isl1 overexpression in wide type mice or intraperitoneal injected zinc robustly upregulated the expression of SerpinA3N in neurons following MCAO. We further found that both the overexpression of Isl1 in neurons and zinc treatment could reduce infarct volume, and improve sensorimotor recovery post-stroke. These findings collectively suggest SerpinA3N as a key mitochondrial redox regulator and reveals zinc-Isl1 signaling as a promising neuroprotective target. These findings not only identified a novel role for SerpinA3N in ferroptosis but also indicated that zinc ion may be a valuable candidate for the development of a potential therapeutic approach.