CMPK2 facilitates pain sensitization by promoting the lactylation and deactivation of cGAS-STING pathway in neuropathic pain

Abstract

Neuropathic pain, a complex condition arising from nerve damage, presents significant challenges in pain management, driving extensive research into its molecular mechanisms. Our mRNA microarray analysis identified cytosine monophosphate kinase 2 (CMPK2) as a key player in the progression of neuropathic pain, but the molecular mechanism remains to be elusive. By western blotting and Q-PCR, we observed a notable upregulation of CMPK2, particularly in microglia of the spinal dorsal horn during neuropathic pain. In vivo and in vitro experiments demonstrated that Cmpk2 deficiency significantly alleviated neuropathic pain and neural injury by increasing the production of type I interferons (IFN-I), which are known for their analgesic properties. Conversely, overexpression of Cmpk2 in microglia led to a marked decrease in IFN-I production in vitro. Further investigation revealed that the transcription factor RUNX1 promoted CMPK2 upregulation in microglia. Mechanistically, we found that CMPK2 exacerbated neuropathic pain by enhancing glycolysis in microglia, resulting in increased lactate production. This accumulation of lactate induced lactylation and deactivation of the stimulator of interferon genes (STING), which was responsible for IFN-I production. These findings suggested that CMPK2 facilitated pain sensitization by promoting microglial glycolysis, resulting in the increased lactylation and deactivation of the cGAS-STING pathway in neuropathic pain, highlighting the potential of targeting CMPK2 for therapeutic intervention in neuropathic pain.