Targeting succinate-driven microglial metabolic reprogramming alleviates neuroinflammation after cerebral ischemia–reperfusion

Abstract Background: Ischemic stroke triggers profound metabolic disturbance and oxidative stress following ischemia–reperfusion, driving secondary neuroinflammation and neuronal injury. Succinate rapidly accumulates under ischemic conditions, yet its active role and receptor-mediated mechanisms in post-stroke inflammation remain unclear. Methods: We integrated targeted metabolomics, clinical association analyses, and mechanistic studies in mouse ischemia–reperfusion models and primary microglia. Genetic and pharmacological approaches, transcriptomic profiling, and extracellular flux analyses were employed to dissect succinate-mediated signaling pathways. A targeted nanoparticle-based delivery system was used to selectively inhibit succinate metabolism in microglia in vivo. Results: Succinate robustly accumulated in ischemic brain tissue and in the circulation of stroke patients, where elevated levels independently predicted poor clinical outcomes. In mice, exogenous succinate aggravated infarct volume, neurological deficits, and neuroinflammation, whereas inhibition of succinate accumulation with malonate conferred significant neuroprotection. Mechanistically, succinate selectively activated microglial succinate receptor 1 (SUCNR1), promoting pro-inflammatory polarization and glycolytic reprogramming. Hypoxia-inducible factor-1α (HIF-1α) was identified as a key downstream effector linking SUCNR1 signaling to metabolic and inflammatory amplification. Genetic or pharmacological disruption of the SUCNR1/HIF-1α axis suppressed microglial inflammation, reduced neuronal apoptosis, and improved functional recovery. Targeted delivery of a succinate metabolism inhibitor further reduced infarct size, neuroinflammation, and neurological deficits in vivo. Conclusion: These findings identify succinate as an active immunometabolic signal that amplifies neuroinflammation after ischemic stroke through a microglial SUCNR1–HIF-1α axis, highlighting a therapeutically tractable pathway for neuroprotection and targeted metabolic intervention.