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Neutrophils, central to periodontal immunity, can undergo functional alterations contributing to disease exacerbation. This study investigates the role of Kr\u00fcppel-like factor 4 (KLF4) in regulating neutrophil aging during the exacerbation of PD by MetS. The analysis of clinical human samples and murine models revealed that MetS enhances the infiltration of senescent neutrophils into periodontal tissues. These neutrophils exhibit a heightened proinflammatory phenotype, including increased secretion of senescence-associated secretory phenotype factors, enhanced formation of neutrophil extracellular traps, and a metabolic reprogramming toward a glycolytic shift. Bioinformatics identified\n                    <jats:italic toggle=\"yes\">KLF4<\/jats:italic>\n                    as a key downregulated gene in comorbid MetS and PD. Adoptive transfer of MetS-derived or\n                    <jats:italic toggle=\"yes\">Klf4<\/jats:italic>\n                    -deficient neutrophils into mice with periodontitis aggravated periodontal inflammation and alveolar bone destruction. In vitro,\n                    <jats:italic toggle=\"yes\">KLF4<\/jats:italic>\n                    knockdown in human neutrophil-like cell lines promoted metabolic reprogramming and proinflammatory phenotype. Through virtual docking and molecular dynamics simulations, we identified rosiglitazone as a candidate compound predicted to stabilize KLF4. This compound alleviated periodontal damage and improved insulin resistance in mice by mitigating the neutrophil aging phenotype and suppressing proinflammatory responses. Critically, all of these therapeutic effects were abolished in\n                    <jats:italic toggle=\"yes\">Klf4<\/jats:italic>\n                    -deficient models. These results indicate that KLF4 is associated with the regulation of neutrophil aging through which MetS exacerbates periodontitis, highlighting KLF4 activation as a promising therapeutic strategy.\n                  <\/jats:p>","DOI":"10.1177\/00220345261429954","type":"journal-article","created":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T06:58:37Z","timestamp":1774076317000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Role of KLF4 in Neutrophil Aging in Periodontitis with Metabolic Syndrome"],"prefix":"10.1177","author":[{"given":"C.","family":"Li","sequence":"first","affiliation":[{"name":"Department of Periodontics, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China"},{"name":"State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China"},{"name":"Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8085-0261","authenticated-orcid":false,"given":"Y.","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Periodontics, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China"},{"name":"State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China"},{"name":"Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Gou","sequence":"additional","affiliation":[{"name":"Department of Periodontics, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China"},{"name":"State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China"},{"name":"Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Q.","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Periodontics, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China"},{"name":"State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China"},{"name":"Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Periodontics, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China"},{"name":"State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China"},{"name":"Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9975-2215","authenticated-orcid":false,"given":"Y.","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Periodontics, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China"},{"name":"State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China"},{"name":"Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"e_1_3_2_2_1","doi-asserted-by":"crossref","unstructured":"Ajoolabady A et al. 2025. 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