The authors propose the Senescent Niche Hypothesis for drug-resistant epilepsy (DRE), implicating a pathological buildup of senescent microglia within the epileptogenic focus. They describe a mechanistic Iron–Senescence Axis in which seizure-related blood–brain barrier disruption leads to chronic iron deposition in parenchyma.
Microglia are proposed to accumulate iron via erythrophagocytosis and endure sub-lethal ferroptotic stress, driving irreversible senescence rather than immediate cell death. Senescent microglia reportedly acquire resistance to ferroptosis through lysosomal iron sequestration and persist, sustaining epileptogenesis through a SASP.
Evidence drawn from human surgical specimens and rodent models purportedly shows that senolytic clearance of senescent cells reduces seizure burden and may prevent epilepsy development. Two therapeutic strategies are evaluated: senolytic therapy with dasatinib plus quercetin (D+Q) to selectively eliminate senescent cells, and the MISTER approach, which involves CSF1R inhibitor–mediated microglial depletion followed by donor cell engraftment to reconstitute the niche.
Uncertainty is noted where data are preliminary, and clinical translation challenges are discussed, including donor cell sources and conditioning.