Recent Insights on Cell-Type-Specific Lactylation Driving Neuropathic Pain Chronification

Neuropathic pain (NP) is a debilitating chronic condition whose molecular mechanisms remain incompletely understood, limiting the development of effective disease-modifying therapies. Lactylation, a lactate-derived post-translational modification of histone and non-histone lysine residues, has recently emerged as a critical epigenetic mechanism that directly couples glycolytic activity to transcriptional reprogramming. Following peripheral nerve injury, four pain-relevant cell populations undergo cell-type-specific glycolytic reprogramming through distinct upstream cascades: the AREG-EGFR-PKM2 axis in dorsal root ganglion sensory neurons, RUNX1-CMPK2 in spinal microglia, Sox9-HK1 in spinal astrocytes, and LDHA in peripheral Th17 cells. The resulting intracellular lactate accumulation drives lactylation through three mechanistic modes: transcriptional activation of pro-nociceptive genes, silencing of analgesic mediators, and direct inactivation of pain-suppressive signaling proteins. A self-reinforcing feedback loop between glycolysis and lactylation further perpetuates the chronic pain state. This review synthesizes current mechanistic evidence, evaluates emerging pharmacological strategies targeting this metabolic epigenetic axis, and discusses outstanding translational challenges including reader protein identification, sex-based variability, and human tissue validation.