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The progression of apical periodontitis was analysed by micro\u2010CT analysis and H&amp;E staining. The expression level and localization of STING in F4\/80<jats:sup>+<\/jats:sup> cells were identified by IHC and immunofluorescence staining. RANKL in periapical tissues was tested by IHC staining. TRAP staining was used to detect osteoclasts. To clarify the effect of STING inhibitor C\u2010176 as an immunotherapeutic drug, mice with apical periodontitis were treated with C\u2010176 and the bone loss was identified by H&amp;E, TRAP, RANKL staining and micro\u2010CT. Bone marrow\u2010derived macrophages (BMMs) were isolated from <jats:italic>Sting<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and WT mice and induced to osteoclasts in a lipopolysaccharide (LPS)\u2010induced inflammatory environment <jats:italic>in vitro<\/jats:italic>. Moreover, WT BMMs were treated with C\u2010176 to determine the effect on osteoclast differentiation by TRAP staining. The expression levels of osteoclast\u2010related genes were tested using qRT\u2010PCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to WT mice, the bone resorption and inflammatory cell infiltration were reduced in exposed <jats:italic>Sting<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. In the exposed WT group, STING was activated mainly in F4\/80<jats:sup>+<\/jats:sup> macrophages. Histological staining revealed the less osteoclasts and lower expression of osteoclast\u2010related factor RANKL in <jats:italic>Sting<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. The treatment of the STING inhibitor C\u2010176 in an apical periodontitis mice model alleviated inflammation progression and bone loss, similar to the effect observed in <jats:italic>Sting<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. Expression of RANKL and osteoclast number in periapical tissues were also decreased after C\u2010176 administration. <jats:italic>In vitro<\/jats:italic>, TRAP staining showed fewer positive cells and qRT\u2010PCR reflected decreased expression of osteoclastic marker, Src and Acp5 were detected during osteoclastic differentiation in <jats:italic>Sting<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and C\u2010176 treated BMMs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>STING was activated and was proven to be a positive factor in bone loss and osteoclastogenesis in apical periodontitis. The STING inhibitor C\u2010176 administration could alleviate the bone loss via modulating local immune response, which provided immunotherapy to the treatment of apical periodontitis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/iej.14057","type":"journal-article","created":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T16:14:32Z","timestamp":1709050472000},"page":"951-965","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["STING inhibition alleviates bone resorption in apical periodontitis"],"prefix":"10.1111","volume":"57","author":[{"given":"Han\u2010Qing","family":"Mao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School &amp; Hospital of Stomatology Wuhan 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