The senescent niche hypothesis: microglial dysfunction and replacement strategies in drug-resistant epilepsy.

Epilepsy is one of the most prevalent neurological disorders, affecting over 70 million individuals worldwide. However, despite the introduction of more than 30 anti-seizure medications over three decades, approximately 30% of patients continue to suffer from drug-resistant epilepsy (DRE). Here, we advance the "Senescent Niche Hypothesis," proposing that the epileptogenic focus in DRE harbors a pathological accumulation of senescent microglia that have lost homeostatic surveillance capacity and acquired a toxic secretory phenotype. We present the "Iron-Senescence Axis" as the mechanistic driver: recurrent seizure-induced blood-brain barrier disruption leads to chronic parenchymal iron deposition; microglia accumulate iron through erythrophagocytosis and sustain sub-lethal ferroptotic stress-characterized by lipid peroxidation, mitochondrial dysfunction, and DNA damage-that drives their irreversible transition to a senescent state rather than acute cell death. Once senescent, these microglia paradoxically acquire resistance to ferroptosis through lysosomal iron sequestration, occupy the niche indefinitely, and perpetuate epileptogenesis via the senescence-associated secretory phenotype (SASP), establishing a positive feedback loop. Converging transcriptomic and experimental evidence from both human surgical specimens and rodent models substantiates this framework, demonstrating that senolytic clearance of senescent cells significantly reduces seizure burden and can prevent epilepsy development. Building on these findings, we evaluate two complementary therapeutic strategies: senolytic therapy using dasatinib plus quercetin (D+Q) for selective elimination of senescent cells, and the Microglial Intervention Strategy for Therapy and Enhancement by Replacement (MISTER) for comprehensive niche reconstitution through CSF1R inhibitor-mediated microglial depletion followed by donor cell engraftment. We critically assess donor cell sources, advances in non-genotoxic conditioning, and CSF1R-inhibitor resistant donor cells that may enable clinical translation. This synthesis argues that targeting the senescent microglial niche may represent a disease-modifying approach that shifts the therapeutic focus from seizure suppression to neuroimmune niche restoration.