ABSTRACT Neuropathic pain (NPP) is a critical clinical challenge with limited therapeutic options. While neuronal mechanisms have been extensively studied, the contribution of oligodendrocyte (OL) homeostasis to NPP pathogenesis is poorly understood. Here, we show that chronic constriction injury (CCI) causes demyelination and downregulation of 3‐phosphoinositide‐dependent kinase 1 (PDK1) in the central nervous system (CNS) in mice. Functional analysis of inducible OL lineage‐specific Pdk1 conditional knockout ( Pdk1 cKO) mice reveals mechanical allodynia and thermal hyperalgesia, a pattern of sensory changes that closely resembles NPP in CCI mice. RNA sequencing (RNA‐seq), morphological, and molecular analyses demonstrate that PDK1 deficiency impairs myelination via the c‐Myc/SOX10 axis. Notably, pharmacological enhancement of remyelination or AAV‐mediated knockdown of c‐Myc restores nodal integrity and alleviates NPP in Pdk1 cKO mice. Our findings establish PDK1‐mediated OL homeostasis as a critical determinant of NPP pathogenesis and identify c‐Myc modulation as a novel therapeutic strategy for NPP.
Qiao et al. (Thu,) studied this question.