Blockage of MLKL prevents myelin damage in experimental diabetic neuropathy

Demyelination is a pathological feature of diabetic neuropathy, a common and painful complication of diabetes, yet the mechanisms underlying diabetes-induced demyelination remain unclear. Here, we show that targeting mixed lineage kinase domain–like protein (MLKL), a protein critical in necroptosis, using Schwann cell–specific genetic knockout, S441A single–amino acid knockin mutation, or pharmacological inhibition all blocked myelin sheath decompaction and prevented the decrease of nerve conduction velocity in streptozotocin-induced diabetic mice. The decompaction of the myelin sheaths of sural nerves was observed in biopsy samples from diabetic patients, and the MLKL-mediated myelin breakdown was activated in human diabetic neuropathy patients. Our study establishes a direct myelin degradation–related role for MLKL in diabetic neuropathy and defines MLKL as a druggable target for developing agents to prevent or treat diabetic neuropathy.