{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:16:16Z","timestamp":1786115776323,"version":"build-2736575974"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Temporomandibular osteoarthritis (TMJ OA) is a degenerative disease with pain, abnormal sound, and restricted mouth - opening. Oxidative stress and ferroptosis contribute to its progression, and inflammatory macrophages in the synovium are crucial. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4), a major Reactive Oxygen Species (ROS) source, is involved in joint disorders, but the mechanism of Nox4 regulating macrophage ferroptosis in TMJ OA is unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>RNA-sequencing was performed on synovial tissues obtained from patients or rats with or without TMJ OA to identify potential therapeutic targets for TMJ OA. Synovial tissues were examined histologically after staining with immunofluorescence. The impact of silencing Nox4 gene expression on inflammatory macrophages was explored. RT-qPCR and Western blotting were used to evaluate the expression of inflammatory and antioxidant genes. Intracellular and mitochondrial ROS were detected using DCFH-DA, DHE, or MitoSOX probes. Mitochondrial membrane potential was detected using the JC-1 probe. Lipid peroxidation and ferroptosis were measured using C11-BODIPY and FerroOrange. RNA-seq was used to analyze the anti-inflammatory mechanisms of the Nox4 inhibitor GLX351322 (40\u00a0\u03bcM) in LPS-stimulated macrophages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In this study, we observed a marked upregulation of Nox4 expression in synovial macrophages from both TMJ OA patients and rats. Inhibition of Nox4 significantly attenuated inflammatory responses through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Upon inhibition of Nox4, ROS production was reduced, accompanied by a reduction in mitochondrial damage. Meanwhile, Nox4 inhibition decreased ferroptosis in inflammatory macrophages by mitigating oxidative stress-induced lipid peroxidation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In this study, we identified Nox4 as a potential therapeutic target in TMJ OA. Targeting Nox4 counld reduce macrophage inflammation by alleviating oxidative stess-induced ferroptosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1854785","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T05:33:52Z","timestamp":1785994432000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Nox4 alleviates TMJ osteoarthritis by restoring redox homeostasis and suppressing ferroptosis in macrophages"],"prefix":"10.3389","volume":"17","author":[{"given":"Yucheng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthodontics, Qingdao University Affiliated Hospital","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qilin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People\u2019s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Pacific State Medical University Russia","place":["Vladivostok, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People\u2019s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuzhuo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People\u2019s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yexin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People\u2019s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanyong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People\u2019s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Department of Oral Surgery, Fengcheng Hospital of Fengxian District, Shanghai Ninth People\u2019s Hospital Fengcheng Branch Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinze","family":"Zhen","sequence":"additional","affiliation":[{"name":"Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People\u2019s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Department of Oral Surgery, Fengcheng Hospital of Fengxian District, Shanghai Ninth People\u2019s Hospital Fengcheng Branch Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"171","DOI":"10.3390\/ijms24010171","article-title":"Temporomandibular joint osteoarthritis: pathogenic mechanisms involving the cartilage and subchondral bone, and potential therapeutic strategies for joint regeneration","volume":"24","author":"Cardoneanu","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41584-018-0109-2","article-title":"Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis","volume":"15","author":"Chen","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2054","DOI":"10.1080\/15548627.2020.1810918","article-title":"Ferroptosis: machinery and regulation","volume":"17","author":"Chen","year":"2021","journal-title":"Autophagy"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3251","DOI":"10.7150\/thno.70623","article-title":"Mitochondria-targeted supramolecular coordination container encapsulated with exogenous itaconate for synergistic therapy of joint inflammation","volume":"12","author":"Chen","year":"2022","journal-title":"Theranostics"},{"key":"B5","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1101\/gad.314674.118","article-title":"Regulation of lipid peroxidation and ferroptosis in diverse species","volume":"32","author":"Conrad","year":"2018","journal-title":"Genes Dev."},{"key":"B6","doi-asserted-by":"publisher","first-page":"867260","DOI":"10.3389\/fimmu.2022.867260","article-title":"The role of M1\/M2 macrophage polarization in rheumatoid arthritis synovitis","volume":"13","author":"Cutolo","year":"2022","journal-title":"Front. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"155282","DOI":"10.1016\/j.phymed.2023.155282","article-title":"Mangiferin attenuates osteoporosis by inhibiting osteoblastic ferroptosis through Keap1\/Nrf2\/SLC7A11\/GPX4 pathway","volume":"124","author":"Deng","year":"2024","journal-title":"Phytomedicine"},{"key":"B8","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.ceb.2017.11.001","article-title":"To eat or not to eat-the metabolic flavor of ferroptosis","volume":"51","author":"Gao","year":"2018","journal-title":"Curr. Opin. Cell Biol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"113644","DOI":"10.1016\/j.fct.2023.113644","article-title":"Cardamonin alleviates chondrocytes inflammation and cartilage degradation of osteoarthritis by inhibiting ferroptosis via p53 pathway","volume":"174","author":"Gong","year":"2023","journal-title":"Food Chem. Toxicol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e162533","DOI":"10.1172\/JCI162533","article-title":"Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity","volume":"134","author":"Greatorex","year":"2023","journal-title":"J. Clin. Invest"},{"key":"B11","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/s41419-024-06503-1","article-title":"Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8(+) T cells","volume":"15","author":"Han","year":"2024","journal-title":"Cell Death Dis."},{"key":"B12","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.cell.2017.11.048","article-title":"Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis","volume":"172","author":"Ingold","year":"2018","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nature14344","article-title":"Ferroptosis as a p53-mediated activity during tumour suppression","volume":"520","author":"Jiang","year":"2015","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1007\/s12192-020-01079-z","article-title":"Nrf2\/ARE is a key pathway for curcumin-mediated protection of TMJ chondrocytes from oxidative stress and inflammation","volume":"25","author":"Jiang","year":"2020","journal-title":"Cell Stress Chaperones"},{"key":"B15","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1007\/s13238-020-00789-5","article-title":"Cystine transporter SLC7A11\/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy","volume":"12","author":"Koppula","year":"2021","journal-title":"Protein Cell"},{"key":"B16","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.freeradbiomed.2007.03.028","article-title":"Regulation of nox and duox enzymatic activity and expression","volume":"43","author":"Lambeth","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.7150\/thno.81240","article-title":"NOX4 is a potential therapeutic target in septic acute kidney injury by inhibiting mitochondrial dysfunction and inflammation","volume":"13","author":"Li","year":"","journal-title":"Theranostics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.freeradbiomed.2023.07.019","article-title":"MAGL inhibition relieves synovial inflammation and pain via regulating NOX4-Nrf2 redox balance in osteoarthritis","volume":"208","author":"Li","year":"","journal-title":"Free Radic. Biol. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"106077","DOI":"10.1016\/j.phrs.2022.106077","article-title":"Main active components of si-miao-yong-an decoction (SMYAD) attenuate autophagy and apoptosis via the PDE5A-AKT and TLR4-NOX4 pathways in isoproterenol (ISO)-Induced heart failure models","volume":"176","author":"Liao","year":"2022","journal-title":"Pharmacol. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"112688","DOI":"10.1016\/j.intimp.2024.112688","article-title":"Targeting G6PD to mitigate cartilage inflammation in TMJOA: the NOX4-ROS-MAPK axis as a therapeutic avenue","volume":"139","author":"Lin","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"102298","DOI":"10.1016\/j.redox.2022.102298","article-title":"Architecture of the NADPH oxidase family of enzymes","volume":"52","author":"Ogboo","year":"2022","journal-title":"Redox Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"101947","DOI":"10.1016\/j.redox.2021.101947","article-title":"NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases","volume":"41","author":"Park","year":"2021","journal-title":"Redox Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.chembiol.2020.03.013","article-title":"The chemistry and biology of ferroptosis","volume":"27","author":"Stockwell","year":"2020","journal-title":"Cell Chem. Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"100904","DOI":"10.1016\/j.jbc.2021.100904","article-title":"Mitochondrial metabolism regulates macrophage biology","volume":"297","author":"Wang","year":"2021","journal-title":"J. Biol. Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1177\/0022034515574770","article-title":"Current understanding of pathogenesis and treatment of TMJ osteoarthritis","volume":"94","author":"Wang","year":"2015","journal-title":"J. Dent. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"6666022","DOI":"10.1155\/2022\/6666022","article-title":"Poldip2\/Nox4 mediates lipopolysaccharide-induced oxidative stress and inflammation in human lung epithelial cells","volume":"2022","author":"Wang","year":"2022","journal-title":"Mediat. Inflamm."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e12992","DOI":"10.1111\/jpi.12992","article-title":"Melatonin alleviates osteoarthritis by regulating NADPH oxidase 4-Induced ferroptosis and mitigating mitochondrial dysfunction","volume":"76","author":"Wang","year":"2024","journal-title":"J. Pineal Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/s41419-022-04775-z","article-title":"Interaction between macrophages and ferroptosis","volume":"13","author":"Yang","year":"2022","journal-title":"Cell Death Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1002\/hep.25746","article-title":"Ferroportin1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores in mice","volume":"56","author":"Zhang","year":"2012","journal-title":"Hepatology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/j.joca.2020.01.007","article-title":"Macrophages regulate the progression of osteoarthritis","volume":"28","author":"Zhang","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1952348","DOI":"10.1155\/2023\/1952348","article-title":"GLX351322, a novel NADPH oxidase 4 inhibitor, attenuates TMJ osteoarthritis by inhibiting the ROS\/MAPK\/NF-\u03baB signaling pathways","volume":"2023","author":"Zhen","year":"2023","journal-title":"Oxid. Med. Cell Longev."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e23589","DOI":"10.1016\/j.heliyon.2023.e23589","article-title":"A ROS-Responsive microsphere capsule encapsulated with NADPH oxidase 4 inhibitor ameliorates macrophage inflammation and ferroptosis","volume":"10","author":"Zhen","year":"2024","journal-title":"Heliyon"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1854785\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T05:33:53Z","timestamp":1785994433000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1854785\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":33,"alternative-id":["10.3389\/fphar.2026.1854785"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1854785","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]},"article-number":"1854785"}}