SYK regulates Schwann cell metabolic reprogramming to promote axonal regeneration in immune-mediated neuropathy

Immune-mediated peripheral neuropathies like acute motor axonal neuropathy (AMAN) drive axonal degeneration through unresolved neuroinflammation, where Schwann cell (SC) metabolic reprogramming fails to support regeneration. While Spleen Tyrosine Kinase (SYK) is recognized for orchestrating immune responses and central glial function, its role in SC immunometabolism remains unknown. We identify SYK as a master regulator bridging neuroinflammation and SC metabolic adaptation in AMAN. SYK was compensatorily upregulated in SCs at sciatic nerve lesions following anti-GD1a IgG-mediated autoimmune injury, suggesting its activation is part of the protective response. Experimental SYK deficiency triggered catastrophic metabolic collapse, impairing glycolysis and oxidative phosphorylation via dysregulated PI3K/AKT/mTOR and HIF-1α/c-Myc signaling. This suppressed glucose uptake, glycolytic enzymes, mitochondrial biogenesis, and electron transport chains, exacerbating mitochondrial damage. Crucially, loss of this SYK response disrupted AMPK/STAT3-dependent mitophagy, causing ROS accumulation and mitochondria-dependent apoptosis, linking metabolic failure to glial degeneration. SYK deficiency further impaired neuro-glial metabolic coupling, reducing lactate production and MCT1-mediated transfer to axons, which compromised axonal bioenergetics. In vivo, targeted SYK knockdown in AMAN mice to block this endogenous upregulation amplified neuroinflammation, impaired nerve bioenergetics, exacerbated muscle atrophy, and worsened neurofunctional deficits. Mechanistically, SYK integrates immune-triggered metabolic reprogramming with mitochondrial quality control to fuel regeneration. These findings establish SYK as a pivotal upstream coordinator of SC metabolism and neuro-immunomodulation that enables metabolic support for axonal regeneration. Targeting SYK to enhance its activity represents a promising metabolic therapy for immune-mediated neuropathy.