Vespakinin-M delineates an AMPK/mTOR-arginine-TCA cycle axis to act as an immunometabolic switch in post-stroke microglia.

Despite advances in recanalization therapy for ischemic stroke, effective neuroprotection against cerebral ischemia-reperfusion injury (CIRI) remains an unmet need, largely due to persistent microglia-driven neuroinflammation and associated oxidative stress. Vespakinin-M (VK) is a naturally neuroprotective peptide isolated from wasp venom that can cross the blood-brain barrier. Although VK has been shown to improve functional outcomes in preliminary stroke models, its underlying mechanisms remain unclear. Here, we show that administration of VK alleviates neuroinflammation and oxidative damage in a mouse stroke model. This neuroprotection is orchestrated by microglial metabolic reprogramming, which shifts their energy metabolism from aerobic glycolysis toward oxidative phosphorylation (OXPHOS) and their functional phenotype from pro-inflammatory M1 to reparative M2. Integrated multi-omics and isotopic tracing uncover that VK redirects arginine metabolism to generate fumarate. This directly couples amino acid catabolism with the tricarboxylic acid (TCA) cycle, thereby restoring mitochondrial bioenergetics and redox balance. Mechanistically, VK activates the energy sensor AMPK while inhibiting the anabolic regulator mTOR. AMPK knockdown partially abolishes the beneficial effects of VK, establishing the AMPK/mTOR axis as the upstream regulator of this arginine-centric metabolic rewiring. Interestingly, VK retains the ability to stimulate de novo arginine synthesis even under arginine-deprived conditions, and its efficacy is synergistically enhanced with arginine supplementation. Together, these findings define an immunometabolic axis-AMPK/mTOR-arginine-TCA cycle coupling-that dictates microglial fate after stroke, and suggests VK as a therapeutic agent capable of concurrently targeting neuroinflammation, mitochondrial dysfunction, and metabolic imbalance.