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While monocyte\u2010derived macrophages (MDMs) are known to adopt a destructive, M1\u2010like pro\u2010inflammatory phenotype, the mechanisms that enable this \u2018runaway\u2019 polarisation by bypassing endogenous negative feedback remain elusive. Here, we identify alternative polyadenylation (APA) as a critical post\u2010transcriptional mechanism driven by pathogens to disrupt macrophage immune control. Integrating single cell RNA sequencing with Sierra APA analysis of human gingival tissues, we uncovered a global shift toward proximal poly(A) site (PAS) usage, indicative of 3\u2032UTR shortening, specifically within the pro\u2010inflammatory MDM subset. This APA remodelling preferentially affected genes essential for cytokine production and inflammatory signalling. In\u00a0vitro, the keystone pathogen\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Porphyromonas gingivalis<\/jats:italic>\n                    <\/jats:styled-content>\n                    similarly induced widespread 3\u2032UTR shortening in macrophages. This shortening systematically eliminated inhibitory miRNA\u2010binding sites, thereby derepressing pro\u2010inflammatory transcripts. Mechanistically, using\n                    <jats:italic>Selenok<\/jats:italic>\n                    as a representative example, we demonstrate that\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>P. gingivalis<\/jats:italic>\n                    <\/jats:styled-content>\n                    induced 3\u2032UTR shortening selectively abolishes repression by miR\u2010320\u20103p, a \u2018brake\u2019 miRNA upregulated in periodontitis, whose binding site is excised by the proximal APA event. Collectively, these findings reveal APA remodelling as a key pathogenic strategy that enables pro\u2010inflammatory macrophages to escape miRNA\u2010mediated suppression, leading to an uncontrolled M1\u2010like state. This \u2018disruption\u2019 of the post\u2010transcriptional braking system provides a new mechanistic rationale for the persistent, destructive inflammation in periodontitis.\n                  <\/jats:p>","DOI":"10.1111\/cpr.70156","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T07:26:48Z","timestamp":1766474808000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Alternative Polyadenylation Drives Runaway Pro\u2010Inflammatory Macrophages in Periodontitis by Enabling Escape From\n                    <scp>miRNA<\/scp>\n                    Repression"],"prefix":"10.1111","volume":"59","author":[{"given":"Jing","family":"Zhang","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 University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilong","family":"Zhao","sequence":"additional","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 University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaru","family":"Deng","sequence":"additional","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 University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyuan","family":"Qu","sequence":"additional","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 University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyi","family":"Zhou","sequence":"additional","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 University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4223-9522","authenticated-orcid":false,"given":"Qin","family":"Zhao","sequence":"additional","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 University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8702-5291","authenticated-orcid":false,"given":"Yufeng","family":"Zhang","sequence":"additional","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 University  Wuhan China"},{"name":"Medical Research Institute School of Medicine, Wuhan University  Wuhan China"},{"name":"Taikang Center for Life and Medical Sciences Wuhan University  Wuhan 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