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Circular RNAs (circRNAs) participate in the regulatory processes of neuropathic pain. Nevertheless, the biological roles of circRNAs in orofacial neuropathic pain remain unexplored. In this study, circRNA sequencing and Real\u2010time quantitative polymerase chain reaction (RT\u2010qPCR) were carried out. Notably, a novel circRNA named circ_lrrc49 was identified to be downregulated following chronic constriction injury of the infraorbital nerve (CCI\u2010ION) in mice on day 14. Subsequent RNA Antisense Purification (RAP)\u2010mass spectrometry and RNA immunoprecipitation found a direct interaction between circ_lrrc49 and increased sodium tolerance 1\u2009homolog (Ist1). Western blot (WB) identified decreased expression of Ist1 on day 14 post\u2010CCI\u2010ION. Considering the known relationship between Ist1 and autophagy, LC3\u2010II and p62 were detected to be upregulated, and an accumulation of autophagosomes were observed at the same time point. Besides, the knockdown of circ_lrrc49 by small interfering RNA (siRNA) reduced Ist1 expression, increased LC3\u2010II, p62 levels and autophagosomes amount, and evoked orofacial mechanical hypersensitivity, which could be counteracted by the Ist1 overexpression. Similarly, the knockdown of Ist1 by siRNA also increased LC3\u2010II and p62 levels and evoked orofacial mechanical hypersensitivity without influence on circ_lrrc49. Moreover, autophagy activation by rapamycin alleviated orofacial mechanical hypersensitivity evoked by CCI\u2010ION or circ_lrrc49 knockdown. In conclusion, our data revealed the existence of a circ_lrrc49\/Ist1\/autophagy signaling axis contributing to the progression of orofacial neuropathic pain. These discoveries reveal the intricate molecular processes that drive orofacial neuropathic pain and identify circ_lrrc49 as a promising target for potential therapeutic interventions.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16075-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.16075","type":"journal-article","created":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T09:32:18Z","timestamp":1707816738000},"page":"1265-1280","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Reduced circ_lrrc49 in trigeminal ganglion contributes to neuropathic pain in mice by downregulating Ist1 and impairing autophagy"],"prefix":"10.1111","volume":"168","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9893-4376","authenticated-orcid":false,"given":"Qingfeng","family":"Tang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology Sichuan University  Chengdu China"},{"name":"Department of Prosthodontics, West China Hospital of Stomatology Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhonghan","family":"Fang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology Sichuan University  Chengdu China"},{"name":"Department of Prosthodontics, West China Hospital of Stomatology Sichuan University  Chengdu China"},{"name":"Guangdong Engineering 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