Targeting microglial glutaminase 1 protects against ferroptosis-driven cognitive impairment in perioperative neurocognitive disorders

Abstract Perioperative neurocognitive disorders (PND) are common neurological complications in elderly surgical patients, for which effective mechanism-based therapies remain lacking. This study identifies ferroptosis, an iron-dependent lipid peroxidation-driven cell death, as a key pathological process in PND, and pharmacological inhibition of ferroptosis with ferrostatin-1 significantly ameliorated cognitive deficits in a surgery and anesthesia-induced mouse model of PND. Moreover, accumulation of glutamate has been observed in the brains of PND mice, which competitively inhibits the neuronal cystine/glutamate antiporter system Xc - (via SLC7A11) to trigger glutathione depletion and ferroptotic cell death. Excessive glutamate production and release are driven by hyperexpression of glutamate-producing enzyme glutaminase 1 (GLS1) in activated microglia via STAT1-dependent transcriptional activation. Pharmacological inhibition of GLS1 with the selective inhibitors CB839 and BPTES suppressed ferroptosis, preserved synaptic plasticity, and improved cognitive performance in PND mice, indicating GLS1 as a potential therapeutic target of PND. Notably, elevated plasma GLS1 levels in PND patients correlated negatively with cognitive test scores ( R 2 = 0.479, p < 0.001) and exhibited moderate diagnostic value across two independent cohorts (AUCs = 0.77 and 0.84), underscoring its clinical relevance as a potential biomarker. Collectively, our findings establish microglial GLS1 as a critical mediator of ferroptosis in PND and highlight its dual promise as a therapeutic target and diagnostic indicator.