SRGN enhances microglia-mediated neuroinflammation and worsens ischemic brain injury. Serglycin (SRGN), a secreted proteoglycan, is upregulated in the ischemic brain, particularly in microglia. SRGN promotes microglial proinflammatory activation, leading to increased neuroinflammation and brain injury. CD44, a receptor for SRGN, is also upregulated in microglia after ischemic stroke. SRGN activates the NF-κB p65 signaling pathway and increases glycolysis in microglia, contributing to neuroinflammation. SRGN deficiency reduces neuroinflammation and improves outcomes in ischemic stroke. These findings suggest that SRGN is a novel therapeutic target for microglia-mediated neuroinflammation in ischemic stroke.SRGN enhances microglia-mediated neuroinflammation and worsens ischemic brain injury. Serglycin (SRGN), a secreted proteoglycan, is upregulated in the ischemic brain, particularly in microglia. SRGN promotes microglial proinflammatory activation, leading to increased neuroinflammation and brain injury. CD44, a receptor for SRGN, is also upregulated in microglia after ischemic stroke. SRGN activates the NF-κB p65 signaling pathway and increases glycolysis in microglia, contributing to neuroinflammation. SRGN deficiency reduces neuroinflammation and improves outcomes in ischemic stroke. These findings suggest that SRGN is a novel therapeutic target for microglia-mediated neuroinflammation in ischemic stroke.