Fatty Acid Binding Protein 5 Mediates Astrocytic Pyroptosis and Neuroinflammation in Epilepsy via cGAS/STING Pathway

ABSTRACT Pyroptosis is an inflammatory type of programmed cell death that may contribute to epilepsy initiation and progression through neuroinflammation. Fatty acid binding protein 5 (FABP5), a lipid chaperone, has been implicated in chronic inflammation. However, whether FABP5 regulates pyroptosis and its pathological role in epilepsy remains uncharacterized. Here, FABP5 was upregulated in astrocytes from temporal lobe epilepsy (TLE) patients, epileptic mice, and primary cells. Deletion of astrocytic Fabp5 significantly attenuated pyroptosis, neuronal loss, and seizure activity in epilepsy. Furthermore, cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway was identified as the downstream signaling of FABP5 by RNA sequencing analysis. Mechanistically, Fabp5 knockdown reduced lipid overload, alleviated mitochondrial dysfunction, and suppressed cGAS‐STING activation. Pharmacological inhibition of mitochondrial fatty acid import recapitulated these protective effects. In contrast, Sting overexpression abolished the reduced pyroptosis level by Fabp5 knockdown, whereas STING inhibition using C‐176 attenuated pyroptosis and seizure activity. Collectively, these findings revealed the regulatory role of FABP5‐cGAS‐STING‐pyroptosis axis in the progression of epilepsy and highlighted the promising potential of astrocytic FABP5 as a therapeutic target for epilepsy.