Reactive astrocytes play an important role in neurological diseases, but theirmolecular and functional phenotypes in epilepsy are unclear. Here, we show thatin patients with temporal lobe epilepsy (TLE) and mouse models of epilepsy,excessive lipid accumulation in astrocytes leads to the formation oflipid-accumulated reactive astrocytes (LARAs), a new reactive astrocyte subtypecharacterized by elevated APOE expression. Genetic knockout of APOE inhibitedLARA formation and seizure activities in epileptic mice. Single-nucleus RNAsequencing in TLE patients confirmed the existence of a LARA subpopulation witha distinct molecular signature. Functional studies in epilepsy mouse models andhuman brain slices showed that LARAs promote neuronal hyperactivity and diseaseprogression. Targeting LARAs by intervention with lipid transport and metabolismcould thus provide new therapeutic options for drug-resistant TLE.