AXL prevents amyloid-β-induced microglial ferroptosis by sustaining SLC2A3-mediated mitochondrial respiration

Dysregulated iron metabolism is a pivotal driver of Alzheimer's disease (AD). Excess iron promotes Aβ aggregation and tau hyperphosphorylation, thereby accelerating disease progression. Serving as the primary iron reservoir in the central nervous system, microglia are intrinsically susceptible to ferroptosis, thereby amplifying neurotoxicity to neighboring neurons. While plaque-associated receptors (e.g., TREM2, AXL, MERTK) govern microglial responses, their precise contribution to metabolic susceptibility to ferroptosis remains elusive. Here, we identify the receptor tyrosine kinase AXL as a critical metabolic safeguard against Aβ-induced ferroptosis in microglia. Mechanistically, our findings indicate that, under our experimental conditions, oAβ exposure is associated with downregulation of AXL in microglia, thereby impairing SLC2A3-dependent glucose uptake and mitochondrial ATP production, which ultimately increases ferroptotic vulnerability. Moreover, through an optimized surface plasmon resonance imaging (SPRi) screening approach, we identified the FDA-approved drug levothyroxine (L-T4) as a potent AXL agonist. L-T4 treatment restores microglial homeostasis, inhibits Aβ-induced ferroptosis, and ameliorates neuropathology in vivo . These findings establish AXL as a novel metabolic safeguard in microglia and highlight L-T4 as a promising therapeutic strategy for AD and other ferroptosis-related disorders via drug repurposing. • Exposure to 5 μM oAβ for 24 hours reduces AXL and SLC2A3 expression, impairs glucose metabolism, and increases ferroptotic vulnerability in microglia. • AXL activation protects microglia against oAβ-induced ferroptosis by sustaining glucose uptake and mitochondrial ATP production. • Levothyroxine (L-T4) binds AXL and rapidly engages AXL/AKT signaling, thereby restoring microglial bioenergetics and suppressing oAβ-induced ferroptosis. • L-T4 treatment rescues synaptic loss and cognitive deficits in 5×FAD mice by blocking ferroptosis propagation.