Amphiregulin contributes to neuropathic pain by enhancing glycolysis that stimulates histone lactylation in sensory neurons

The genesis of neuropathic pain after peripheral nerve injury is associated with changes in gene expression and cell metabolism in sensory neurons and the release of inflammatory cytokines. Here, we connected glycolytic metabolism induced by the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) to histone lactylation and changes in gene expression that promote chronic neuropathic pain. In both male and female mice subjected to peripheral nerve injury, the mRNA and protein abundance of AREG and its receptor EGFR was increased in dorsal root ganglia (DRGs). AREG-EGFR signaling induced glycolytic metabolism by activating the kinase PKM2. An increase in the glycolytic byproduct lactate facilitated lactylation of the histone lysines H3K18 and H4K12 by the lactyltransferase p300 in DRG neurons. These modifications promoted the expression of genes encoding various proinflammatory and pronociceptive proteins that contribute to the development and maintenance of pain. Deletion or knockdown of AREG or pharmacologically inhibiting EGFR, PKM2, or p300 alleviated neuropathic pain in mice and attenuated the injury-induced hyperexcitability of nociceptive neurons. Targeting this metabolically driven epigenetic mechanism may be a way to treat neuropathic pain in patients.