<p>Neuropathic pain is a type of chronic pain caused by abnormal pathological changes related to tissue damage or neuroinflammation in the nervous system. Peripheral axon injury often leads to symptoms of neuropathic pain, and many studies have shown that axonal regeneration-related genes (ARRGs) in the dorsal root ganglion (DRG) also participate in the regulation of neuropathic pain. However, the role of ARRG-based signatures in the prediction, diagnosis, and treatment of neuropathic pain remains unclear. In this study, we established a neuropathic pain signature in rat DRGs based on four ARRGs (HSPB1, SCN11A, GAP43, and NRG1), utilizing the least absolute shrinkage and selection operator (LASSO) and support vector machine–recursive feature elimination (SVM-RFE) regressions for the GSE24982 dataset, and employed the GSE30691 and GSE2636 datasets, conducting fundamental experiments to substantiate the accuracy of this signature. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) provided valuable insights into the potential mechanisms through the underlying biology of the signature. The analysis of immune infiltration demonstrated a “crosstalk” between the predictive role of the ARRG signature in neuropathic pain and the intrinsic immune mechanisms. The ARRGs–miRNA–lncRNA networks suggested potential mechanisms through which noncoding RNAs could function in the peripheral DRG to mediate neuropathic pain. Based on the drugs predicted from the fourARRG targets, we explored the HSPB1 protein inhibitor Apatorsen to determine whether it could effectively alleviate mechanical and thermal hyperalgesia in models of both neuropathic pain and inflammatory pain. In summary, our research identified novel therapeutic targets and biomarkers in DRG for neuropathic pain and a potential analgesic drug, Apatorsen, which could facilitate the transition towards clinical application.</p>