Pyruvate kinase activates SARM1 to exacerbate axonal degeneration in diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a prevalent and disabling complication of diabetes, characterized by progressive axonal degeneration. However, the molecular link between hyperglycemia and axon injury remains unclear. Here, we identify pyruvate kinase M (PKM) as a direct metabolic activator of the NADase SARM1 under high-glucose conditions. Proteomic and biochemical analyses reveal that PKM binds the TIR domain of SARM1 via its C-terminal region, allosterically enhancing NADase activity independently of PKM’s glycolytic role. In dorsal root ganglion (DRG) neurons, hyperglycemia strengthens the PKM–SARM1 interaction, driving NAD⁺ depletion, axonal fragmentation, and sensory dysfunction. Genetic depletion of PKM protects against streptozotocin-induced neuropathy, preserving nerve fiber density, restoring NAD⁺ levels, and alleviating mechanical allodynia. Most notably, we developed Pep-SP1, a competitive inhibitory peptide derived from residues 645–655 of the SARM1 TIR domain, which selectively disrupts the PKM–SARM1 interaction without impairing PKM metabolism or SARM1 catalytic activity. Systemic delivery of Pep-SP1 attenuates axonal degeneration and improves sensory outcomes in diabetic mice. By targeting a disease-potentiating interface, we expand therapeutic strategies beyond catalytic and allosteric inhibition, offering a mechanistically distinct avenue for axon protection with broad relevance to metabolic and neurodegenerative disorders.