AXL Promotes Ischemic Myelin Repair Through Alleviating Myelin Debris Deposition and Lipid Droplets Accumulation

Microglial AXL drives white matter repair after stroke by orchestrating the cleanup of myelin debris. Mechanistically, AXL signals through EGR1 to boost Smpd1 transcription, regulating sphingolipid metabolism and preventing lipid droplet toxicity. Restoring the pathway with ASM therapy mitigates damage, positioning AXL as a key node for therapeutic intervention. ABSTRACT Ischemic white matter injury leads to long‐term neurological deficits but currently lacks effective therapies. Although AXL has been implicated in debris clearance and inflammatory regulation, its role in post‐stroke myelin repair remains unclear. Here, we report robust upregulation of microglial AXL in mice after tMCAO. Microglial AXL cKO mice exhibited worse motor and cognitive deficits up to 28 days after tMCAO, accompanied by more severe white matter damage, increased myelin debris, and greater lipid droplets (LDs) accumulation in microglia than WT controls. Longitudinal analysis showed that AXL‐deficient microglia had reduced early phagocytic capacity but increased LDs accumulation and lipid peroxidation at later stages. Transcriptomic profiling revealed altered inflammatory and sphingolipid metabolism pathways in AXL‐deficient microglia. Mechanistically, AXL regulates Smpd1 transcription via EGR1, thereby modulating sphingolipid metabolism and LDs accumulation. Remarkably, supplement with ASM (the Smpd1‐encoded enzyme) in AXL cKO mice reduced LDs accumulation and attenuated ischemic white matter injury. Collectively, these findings identify microglial AXL as an endogenous regulator of myelin repair after ischemic stroke. Microglial AXL drives white matter repair after stroke by orchestrating the cleanup of myelin debris. Mechanistically, AXL signals through EGR1 to boost Smpd1 transcription, regulating sphingolipid metabolism and preventing lipid droplet toxicity. Restoring the pathway with ASM therapy mitigates damage, positioning AXL as a key node for therapeutic intervention. ABSTRACT Ischemic white matter injury leads to long-term neurological deficits but currently lacks effective therapies. Although AXL has been implicated in debris clearance and inflammatory regulation, its role in post-stroke myelin repair remains unclear. Here, we report robust upregulation of microglial AXL in mice after tMCAO. Microglial AXL cKO mice exhibited worse motor and cognitive deficits up to 28 days after tMCAO, accompanied by more severe white matter damage, increased myelin debris, and greater lipid droplets (LDs) accumulation in microglia than WT controls. Longitudinal analysis showed that AXL-deficient microglia had reduced early phagocytic capacity but increased LDs accumulation and lipid peroxidation at later stages. Transcriptomic profiling revealed altered inflammatory and sphingolipid metabolism pathways in AXL-deficient microglia. Mechanistically, AXL regulates Smpd1 transcription via EGR1, thereby modulating sphingolipid metabolism and LDs accumulation. Remarkably, supplement with ASM (the Smpd1 -encoded enzyme) in AXL cKO mice reduced LDs accumulation and attenuated ischemic white matter injury. Collectively, these findings identify microglial AXL as an endogenous regulator of myelin repair after ischemic stroke. Advanced Science, EarlyView.