Enhancer profiling uncovers Jmjd1c as an essential suppressor in neuropathic pain by targeting Socs3

Neuropathic pain (NP) is a chronic debilitating disease caused by nerve damage or various diseases, significantly impairs patients' quality of life. Super-enhancers (SEs) are important cis-regulatory elements, but how they affect NP remains elusive. Therefore, we aim to explore the molecular mechanism by which SEs are involved in NP progression and identify potential drug candidate targets. We first established a NP model in rats, and subsequently performed H3K27ac ChIP-Seq and RNA-Seq on their spinal cord tissues to analyze the active enhancers. By integrated analysis of ChIP-seq data and RNA-seq data, we clarified a series of SE-associated genes involved in NP progression. qPCR and double immunofluorescence staining results suggested that <i>Jmjd1c</i> mRNA and protein levels were significantly down-regulated in the NP model. In addition, a dual-luciferase reporter assay showed that <i>KLF15</i> could activate <i>Jmjd1c</i> transcription by binding to the SE of <i>Jmjd1c</i>. Functionally, enhanced <i>Jmjd1c</i> can inhibit the levels of inflammatory cytokines such as IL-6, TNF-α, IL-1β, and inhibited the progression of NP, whereas silencing <i>Jmjd1c</i> had the opposite effect. Mechanistic exploration identified <i>Jmjd1c</i> exerted its anti-NP effect via positively regulating <i>Socs3</i> expression by increasing the activity of H3K9 demethylation, and the <i>Jmjd1c/Socs3/JAK/STAT3</i> regulatory pathway was finally validated as downstream effectors. In conclusion, our study suggests that SE-associated <i>Jmjd1c</i> was suppressed during NP progression due to the decreased recruitment of <i>KLF15</i>. The reduction of <i>Jmjd1c</i> downregulated <i>Socs3</i> through the demethylation of H3K9 at <i>Socs3</i> promoter region, leading to NP progression.