ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
NOX2 Exacerbates Periodontitis via JAK2-STAT3-mediated Ferroptosis of Gingival Epithelial Cells
Provisionally accepted
- 1Chongqing Medical University Key Laboratory of Clinical Laboratory Diagnostics Ministry of Education, Chongqing, China
- 2First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing, China
- 3The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing, China
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Background: 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 in vivo. Methods: Periodontitis was induced in C57BL/6 mice by silk ligation and an in vitro model was established using lipopolysaccharide derived from Porphyromonas gingivalis (Pg-LPS) -stimulated CA9-22 gingival epithelial cells. Expression levels of NOX2, GPX4, SLC7A11 and NF-κB 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&E and TRAP staining. Results: NOX2 expression was significantly elevated in the gingival tissues of periodontitis patients, the mouse model and Pg-LPS-stimulated CA9-22 cells. Mechanistically, we confirmed that Pg-LPS upregulated NOX2 by triggering the TLR4/NF-κB pathway. Gene silencing of NOX2 in vitro effectively suppressed ferroptosis as indicated by reduced ROS/MDA levels and restored expression of GPX4 and SLC7A11. Furthermore, H2O2 added to cell cultures to mimic ROS effects demonstrated that NOX2 mediated ferroptosis via ROS generation and JAK2-STAT3 activation. In vivo, pharmacological inhibition of NOX2 attenuated ferroptosis, mitigated alveolar bone loss, and ameliorated periodontal pathology in mice. Conclusions: NOX2 activation promoted periodontitis by driving ferroptosis via the ROS/JAK2-STAT3 pathway, highlighting its potential as a novel therapeutic target.
Keywords: bioinformatics, ferroptosis, JAK2-STAT3 pathway, NOX2, Periodontitis
Received: 12 Nov 2025; Accepted: 09 Feb 2026.
Copyright: © 2026 Ping, Wang, Yang, Li, Li, Zhang, Wang and He. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wei Wang
Yujuan He
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