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The prior research demonstrates that pro\u2010inflammatory changes in macrophages under estrogen deficiency exacerbate periodontitis. However, the primary environmental factors contributing to the alteration of monocyte\u2010macrophages remain unknown. Recent studies, including animal models and clinical trials, have found a correlation between accumulation of visceral adipose tissue (VAT) and periodontitis progression in postmenopausal women. In estrogen\u2010deficient mice, macrophages in VAT show a pro\u2010inflammatory state. Removing VAT alleviates periodontitis in OVX mice. DNA methylation sequencing shows increased methylation in macrophages, especially\n                    <jats:italic>Jazf1<\/jats:italic>\n                    hypermethylation, inhibiting its expression and promoting inflammation. Subsequently, small extracellular vesicles (sEVs) derived from pro\u2010inflammatory macrophages further intensify M1\u2010like polarization in resting macrophages, carrying inflammatory microRNAs like miR\u201030e\u20105p. Overall, this study proposes a novel perspective: periodontal pathogens act as initial triggers for inflammation, while chronic systemic inflammation, worsened by estrogen deficiency, is the main factor that exacerbates periodontitis. Pro\u2010inflammatory macrophages in VAT release sEVs, which activate resting macrophages into a pro\u2010inflammatory state upon encountering periodontal pathogens, resulting in persistent inflammation. Addressing the root causes of this dysregulation can lead to new therapeutic strategies for periodontitis and systemic inflammatory conditions, particularly in postmenopausal women.\n                  <\/jats:p>","DOI":"10.1002\/advs.202506121","type":"journal-article","created":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T12:59:16Z","timestamp":1752325156000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Adipose Tissue Macrophages as Initiators of Exacerbated Periodontitis in Estrogen\u2010Deficient Environments via the Amplifier Extracellular Vesicles"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4822-3292","authenticated-orcid":false,"given":"Danfeng","family":"Li","sequence":"first","affiliation":[{"name":"Hospital of Stomatology Sun Yat\u2010sen University  Guangzhou 510055 China"},{"name":"Guangdong Provincial Key Laboratory of Stomatology  Guangzhou 510080 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