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• ADAR3 is downregulated in neuropathic pain. • ADAR3 suppresses inflammation and pyroptosis triggered by neuropathic pain. • NLRP3 is the downstream gene of ADAR3 in neuropathic pain. Adenosine deaminase acting on RNA 3 (ADAR3) was known as a prognosis factor in gliomas, while its function on neuropathic pain (NP) is barely investigated. Therefore, our present study concentrated on the potential role of ADAR3 in NP. The chronic constriction injury (CCI) mouse model was established to induce NP in vivo. Behavioral experiments were carried out to analyze mechanical allodynia and thermal hyperalgesia. RT-qPCR and western blotting assays were used to detect the mRNA and protein expressions. The ADAR3-overexpressed adenovirus was injected into the CCI mice through an intrathecal catheter. ELISA was used to detect the contents of IL (interleukin)-6, IL-10, TNF (tumor necrosis factor)-α, IL-1β and IL-18. NLR Family Pyrin Domain Containing 3 (NLRP3) was predicted to be the target gene of ADAR3 using Starbase. The interaction between ADAR3 and NLRP3 was verified via RNA pull-down, RNA immunoprecipitation and Pearson's correlation coefficient assays. Immunohistochemical staining assay visualized the expressions of NLRP3 and caspase1. Allodynia and hyperalgesia were exacerbated in the CCI mice, which implied a successful establishment of the NP model, while ADAR3 expression level was suppressed. After injecting ADAR3-overexpressed adenovirus into the CCI mice, allodynia, hyperalgesia and inflammation were all restrained. Moreover, NLRP3 was verified to negatively correlated with ADAR3. Additionally, the pyroptosis-related protein NLRP3, ASC, caspase1, IL-1β, IL-18 and GSDMD expressions were all decreased by ADAR3. In conclusion, ADAR3 alleviated inflammation and pyroptosis of NP through targeting NLRP3, which suggested a therapeutical target for NP. [ABSTRACT FROM AUTHOR]