ACVR1-mediated glycolytic reprogramming promotes histone lactylation and neuronal pyroptosis in neuropathic pain {ChIP-seq]

Chronic neuropathic pain arises from intricate neuroimmune interactions, yet the molecular mechanisms remain poorly defined. Here, we identify activin A receptor type 1 (ACVR1) as a key neuronal driver of a metabolic-epigenetic program in the spinal dorsal horn following peripheral nerve injury. Nerve injury induced ACVR1 upregulation, which enhanced glycolytic flux and lactate production. Lactate served as a substrate for ACVR1-dependent histone H3 lysine 18 lactylation (H3K18la), an epigenetic modification enriched at promoters of pro-nociceptive genes, thereby activating a neuroinflammatory transcriptional program. Multi-omics integration and functional assays revealed that this pathway engaged the NLRP3 inflammasome and triggered neuronal pyroptosis. Pharmacological inhibition of ACVR1 or blockade of lactylation suppressed inflammasome activation, reduced neuroinflammation, and alleviated pain hypersensitivity in vivo. These findings delineate a pivotal neuronal ACVR1-glycolysis-H3K18la axis that orchestrates neuroimmune cross-talk in neuropathic pain, providing a potential metabolic-epigenetic target for therapeutic intervention. Spinal cord in three treatment groups: sham, SNI, SNI+LDN193189