Histone lactylation contributes to neuropathic pain by facilitating m ⁶ A reader protein IGF2BP2 expression in DRG sensory neurons

Histone lactylation is a novel lactate-dependent histone mark that plays an important role in regulating gene expression. However, its role in neuropathic pain remains elusive. Here, we report that Histone 3 lysine 18 lactylation (H3K18la) is a key factor in initiating and advancing neuropathic pain. Peripheral nerve injury increased the levels of H3K18la level in injured dorsal root ganglia (DRGs) of mice. This upregulation led to increased binding at the Igf2bp2 CpG island, which in turn activated Igf2bp 2 transcription. Increased IGF2BP2 levels subsequently stabilized Cct2 mRNA and upregulated CCT2 protein expression. Pharmacological inhibition of H3K18la activity by injection of 2-DG or knockdown of Igf2bp2 decreased IGF2BP2 levels. This resulted in Cct2 instability in the DRG of CCI male and female mice. Concurrently, mechanical and thermal pain hypersensitivity was attenuated. In contrast, injecting sodium lactate into the uninjured DRG increased H3K18la and IGF2BP2 levels subsequently elevating CCT2 protein and inducing neuropathic-pain-like behaviors. Our results reveal that histone lactylation contributes to dysfunctional gene expression in nociceptive pathways, suggesting that targeting histone lactylation could provide a new therapeutic strategy for neuropathic pain. Significance statement Histone lactylation’ role in neuropathic pain remains unknown. Here, we found an increase of Histone 3 lysine 18 lactylation (H3K18la) within dorsal root ganglion (DRG) following peripheral nerve injury. The observed effect appears to underlie H3K18la’ capacity to upregulate Igf2bp2, an RNA m 6 A binding protein, which subsequently enhances CCT2 expression. Moreover, the pharmacological inhibiting H3K18la in the DRG significantly alleviate pain hypersensitivity. These observations highlight the role of histone lactylation in neuropathic pain pathogenesis and support the strategy of targeting histone lactylation activity or expression for treating neuropathic pain.