{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T06:02:07Z","timestamp":1789970527988,"version":"4.0.1"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82572525"],"award-info":[{"award-number":["82572525"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372195"],"award-info":[{"award-number":["82372195"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Periodontitis (PD) is a destructive inflammatory disease driven by the collapse of immune homeostasis and alveolar bone resorption. Isobavachalcone (IBC) is a naturally occurring prenylated chalcone belonging to the plant flavonoid family, mainly enriched in the mature seeds of\n                      <jats:italic>Cullen corylifolium<\/jats:italic>\n                      , with reported anti-inflammatory, antioxidant, and osteoprotective activities. However, the molecular mechanisms by which IBC modulates the macrophage-mediated immune response and cellular survival within the chronic inflammatory microenvironment of periodontitis remain poorly understood. This study aimed to investigate the therapeutic efficacy of IBC on periodontitis and elucidate its potential molecular targets, with a specific focus on macrophage ferroptosis and immunometabolic regulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Experimental periodontitis was induced in rats by ligation combined with Porphyromonas gingivalis LPS topical application. Alveolar bone parameters were analyzed via micro-CT and histology. Network pharmacology, molecular dynamics (MD) simulations, cellular thermal shift assays (CETSA) and microscale thermophoresis (MST) assays were integrated to screen and validate the physical binding targets of IBC. Single-cell RNA sequencing (scRNA-seq) analysis and clinical samples were utilized to confirm translational relevance, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      RAW264.7 macrophage models were employed for mechanistic verification.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vivo<\/jats:italic>\n                      , subgingival administration of IBC significantly reduced alveolar bone loss, suppressed inflammatory infiltration, and promoted macrophage M2 polarization. Bioinformatic screening combined with MD simulations and CETSA validated PTGS2 as the direct functional target of IBC. Human scRNA-seq and clinical specimen analyses confirmed that PTGS2 expression is predominantly enriched in periodontal macrophages and inversely correlates with the expression of glutathione peroxidase 4 (GPX4). Mechanistically, IBC physically bound and antagonized PTGS2, thereby blocking the downstream JNK\/p38 MAPK phosphorylation cascade and breaking the noxious reactive oxygen species (ROS) amplification loop. Consequently, IBC restored mitochondrial iron transport homeostasis (downregulating TFR1\/MFRN1 and upregulating CISD1), stabilized GPX4, and prevented macrophage ferroptosis, which collectively drove the transition to a reparative M2 phenotype. Crucially, genetic overexpression of PTGS2 abolished these protective effects against ferroptosis\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>IBC acts as a potent protective agent against periodontitis by directly targeting the PTGS2\u2013MAPK\u2013ROS\u2013GPX4 axis, thereby inhibiting macrophage ferroptosis and restoring periodontal immune homeostasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1913548","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:34:48Z","timestamp":1789968888000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Isobavachalcone attenuates experimental periodontitis by suppressing PTGS2-associated macrophage ferroptosis and restoring periodontal immune homeostasis"],"prefix":"10.3389","volume":"17","author":[{"given":"Ruolan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction and Stomatology Institute of Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanye","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, School of Medicine, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction and Stomatology Institute of Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyan","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, School of Medicine, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, School of Medicine, Nankai University","place":["Tianjin, China"]},{"name":"Department of General Surgery, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, School of Medicine, Nankai University","place":["Tianjin, China"]},{"name":"Department of General Surgery, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction and Stomatology Institute of Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"875091","DOI":"10.3389\/fmicb.2022.875091","article-title":"Periodontitis induced by orthodontic wire ligature drives oral microflora dysbiosis and aggravates alveolar bone loss in an improved murine model","volume":"13","author":"Ai","year":"2022","journal-title":"Front. 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