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Mitochondrial cristae ultrastructure enables ATP synthase organization for adaptive energy production. This process is critical for regulating microglia mediated neuroinflammation in ischemic stroke pathology. However, therapeutic strategies targeting cristae remodeling remain unexplored. We identified a chemical probe, icariin II (ICS), which restores mitochondrial cristae by targeting triose phosphate isomerase 1 (TPI1). ICS-induced TPI1 conformational switching recruits ATP5MF to drive F₁F_o-ATP synthase dimerization, thereby resulting in cardiolipin-mediated membrane curvature generation for cristae morphogenesis. Functionally, TPI1-targeted intervention reprograms microglial immunometabolism by rescuing oxidative phosphorylation, suppressing mtDNA-STING neuroinflammation, and promoting M2 polarization. In vivo, pharmacologically targeting TPI1 inhibits microglial activation to reverse the pathological processes in a middle cerebral artery occlusion rat model (male only). Further, evidence from stroke patients suggests an association between TPI1 and microglial activation. Collectively, our findings reveal that cristae plasticity is a promising therapeutic target for mitochondrial disorders, with TPI1 as a central regulator for ischemic stroke.