A Novel Approach to Neuropathic Pain Treatment: Lactylation Targeting Microglia

Neuropathic pain (NP) is a high-prevalence syndrome of chronic pains around the world. Currently, the efficacy of existing medications is suboptimal, and their use is associated with potential adverse effects, posing a major challenge for current clinical practice. Recent research sufficiently suggests that central regulations of pathogenesis and progression of NP are caused and regulated by abnormal activation of microglia. The new paradigm of this field is the use of the emerging mechanism of the epigenetic modification, namely the lactylation. The paper under review focuses on microglial lactylation, which systematically elucidates the molecular processes underlying lactylation and its critical role in NP pathogenesis. It has been shown that in the conditions of NP-induced abnormal lactate accumulation in microglia stimulates pro-inflammatory gene expression by lactylation of histone H4 lysine 12 (H4K12) and creates a vicious cycle of metabolism-epigenetics-neuroinflammation. This review further explores the possibilities of therapeutic value of intervening in the lactylation pathway. Targeted intervention strategies for this pathway hold promise in breaking the pathological vicious cycle of NP, advancing treatment paradigms from mere symptom control toward disease-modifying therapies. This will provide an essential theoretical basis and translational study pathways to create highly effective and precisely targeted new treatment medicine for NP.