ZBTB18 Dysfunction Promotes Neuropathic Pain via CHD4-based Epigenetic Disinhibition of CLIC1 Channels in Sensory Neurons.

Nerve injury-induced reprogramming of sensory neuron gene expression is a key driver of neuropathic pain. However, the transcriptional networks that orchestrate this maladaptive plasticity remain largely undefined. Here, we identify the transcriptional repressor ZBTB18 as a critical regulator of this pathogenic process. Peripheral nerve injury markedly downregulated the level of ZBTB18 in the injured trigeminal ganglion (TG) of rats. Restoring ZBTB18 expression reverses injury-induced mechanical allodynia, while its knockdown in naive TG neurons is sufficient to recapitulate neuropathic pain symptoms. Mechanistically, ZBTB18 directly represses Clic1 transcription by engaging a specific silencer element within its promoter. This repression is achieved through the recruitment of the nucleosome remodeling and deacetylase (NuRD) complex, an interaction mediated by the ZBTB18 BTB domain and the chromodomain helicase DNA-binding protein 4 (CHD4). Disruption of this recruitment abrogates histone H3K27ac deacetylation at the Clic1 promoter, enhancing RNA polymerase II occupancy and driving Clic1 expression. Consequently, nerve injury-induced loss of ZBTB18 relieves this epigenetic brake, leading to CLIC1 upregulation, increased chloride channel activity, and hyperexcitability of TG neurons that underlies mechanical hypersensitivity. In summary, these findings reveal a novel ZBTB18/NuRD/CLIC1 epigenetic axis in neuropathic pain and highlight this transcriptional pathway as a potential target for therapeutic intervention.