Microglial GPR35 Ameliorates Epileptogenesis and Neuroinflammation via PDGFA Domain 2 Signaling

ABSTRACT Neuroinflammation is a critical driver of epileptogenesis and cognitive dysfunction in epilepsy; however, targeted anti‐inflammatory therapies remain limited. In this study, we demonstrate that microglial GPR35 orchestrates neuroinflammatory epileptic networks through platelet‐derived growth factor A (PDGFA)‐dependent signaling. Single‐nucleus RNA sequencing of patients with temporal lobe epilepsy (TLE) and pharmacological models reveals selective GPR35 upregulation in disease‐associated microglia. GPR35 deficiency exacerbates seizure susceptibility and cognitive deficits. We further demonstrate that GPR35 activation mitigates seizures, suppresses hippocampal neuroinflammation, and alleviates cognitive deficits. Mechanistically, kynurenic acid–activated GPR35 specifically interacts with PDGFA domain 2 via defined binding motifs, thereby suppressing PDGFA degradation through the ubiquitin–proteasome pathway. This cascade triggers PI3K–AKT signaling and subsequently inhibits pro‐inflammatory responses. Conversely, GPR35 deficiency disrupts this pathway of neuroinflammation, and hyperexcitability. PDGFA overexpression phenocopies GPR35 activation, attenuating inflammation and epileptogenesis. These findings establish GPR35 as a critical modulator of epileptic networks via PDGFA‐dependent anti‐inflammatory signaling, bridging neuroimmune crosstalk with the pathophysiology of epilepsy. Our study identifies GPR35 as a druggable target capable of disrupting the vicious cycle of inflammation and hyperexcitability in epilepsy, offering a dual therapeutic strategy to alleviate seizures and cognitive comorbidities.