ZBTB16 Improves Myelin Damage in Diabetic Peripheral Neuropathy by Inhibiting Schwann Cell Dedifferentiation

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes characterized by demyelination and axonal degeneration, yet effective therapies remain limited. This study investigates the role of Zinc finger and BTB domain-containing 16 (ZBTB16) in myelin damage during DPN. We identified that ZBTB16 was significantly elevated in sciatic nerves of streptozotocin (STZ)-induced diabetic mice via mRNA sequencing. In vivo, adeno-associated virus (AAV9)-mediated overexpression of ZBTB16 under the myelin protein zero (MPZ) promoter improved motor nerve conduction velocity and sensory nerve action potential, reduced demyelination and suppressed the expression of Schwann cell dedifferentiation markers (p-cJUN, p75NTR) while enhancing myelin markers (MBP, P0). ZBTB16 also ameliorated oxidative stress (restoring GSH/GSSG ratio, reducing ROS) and mitochondrial dysfunction (normalizing ATP/mtDNA levels, electron transport chain complexes I-IV). In vitro, ZBTB16 overexpression in high glucose (HG)-treated Schwann cells inhibited apoptosis, dedifferentiation, and mitochondrial defects. Mechanistically, ZBTB16 transcriptionally activated PTCD1 (a mitochondrial regulator) by binding its promoter, confirmed via dual-luciferase assays. Knockdown of PTCD1 abolished ZBTB16's protective effects on Schwann cell differentiation and mitochondrial function. These findings demonstrated that ZBTB16 attenuates DPN by maintaining mitochondrial integrity via PTCD1 activation, thereby inhibiting Schwann cell dedifferentiation and myelin loss. Our study suggests ZBTB16 as a promising target for ameliorating DPN-associated myelin injury.