{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T20:46:57Z","timestamp":1793652417479,"version":"4.5.1"},"reference-count":83,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Ferroptosis is a novel form of regulated cell death driven by lipid peroxidation and oxidative stress, and has been implicated in the pathogenesis of periodontitis. The purpose of this study was to elucidate mechanisms by which NADPH oxidase 2 (NOX2) promotes ferroptosis in gingival epithelial cells and contributes to periodontitis\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Periodontitis was induced in C57BL\/6 mice by silk ligation and an\n                      <jats:italic>in vitro<\/jats:italic>\n                      model was established using lipopolysaccharide derived from\n                      <jats:italic>Porphyromonas gingivalis<\/jats:italic>\n                      (Pg-LPS) -stimulated CA9\u201322 gingival epithelial cells. Expression levels of NOX2, GPX4, SLC7A11 and NF-\u03baB and JAK2-STAT3 pathway-related proteins were assessed by Western blotting. Lipid peroxidation was quantified by measuring malondialdehyde (MDA) levels and intracellular reactive oxygen species (ROS) were measured using the fluorescent probe DCFH-DA and detected via microscopy and spectrophotometry. The effects of NOX2 on alveolar bone loss were evaluated by micro-CT analysis and H&amp;amp;E and TRAP staining.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      NOX2 expression was significantly elevated in the gingival tissues of periodontitis patients, the mouse model and Pg-LPS-stimulated CA9\u201322 cells. Mechanistically, we confirmed that Pg-LPS upregulated NOX2 by triggering the TLR4\/NF-\u03baB pathway. Gene silencing of NOX2\n                      <jats:italic>in vitro<\/jats:italic>\n                      effectively suppressed ferroptosis as indicated by reduced ROS\/MDA levels and restored expression of GPX4 and SLC7A11. Furthermore, H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      added to cell cultures to mimic ROS effects demonstrated that NOX2 mediated ferroptosis via ROS generation and JAK2-STAT3 activation.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , pharmacological inhibition of NOX2 attenuated ferroptosis, mitigated alveolar bone loss, and ameliorated periodontal pathology in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>NOX2 activation promoted periodontitis by driving ferroptosis via the ROS\/JAK2-STAT3 pathway, highlighting its potential as a novel therapeutic target.<\/jats:p>\n                  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