{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:07:21Z","timestamp":1793275641185,"version":"4.5.0"},"reference-count":107,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"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:p>Rheumatoid arthritis (RA) is a systemic autoimmune disorder marked by persistent synovitis and the degradation of joint cartilage and surrounding bone due to inflammation. A variety of immune cells, particularly macrophages, are involved in the initiation and maintenance of inflammation in RA, along with leukocyte adhesion and migration, matrix breakdown, and neovascularization. Environmental and internal stimuli drive macrophages to polarize into two major phenotypes: M1, which exerts strong bactericidal effects and contributes to chronic inflammation and tissue injury, and M2, which inhibits inflammation and facilitates tissue repair. The dysregulation of M1\/M2 macrophage polarization is a key contributor to the pathogenesis and disease progression of RA. Plant metabolites are typically characterized by multi-component, multi-target, and multi-pathway actions, and their underlying mechanisms may include regulation of immune function, especially the balance of macrophage polarization. Current evidence indicates that such metabolites may provide certain therapeutic benefits and a relatively manageable safety profile in the management of RA and related disorders. In this review, we summarize the potential mechanisms by which various plant metabolites modulate macrophage function and polarization under inflammatory conditions, providing evidence for their clinical application in RA treatment and offering new insights into precision therapy for RA.<\/jats:p>","DOI":"10.3389\/fphar.2025.1651763","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T05:29:43Z","timestamp":1760678983000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Modulating M1\/M2 macrophage polarization with plant metabolites: a therapeutic strategy for rheumatoid arthritis"],"prefix":"10.3389","volume":"16","author":[{"given":"Yuanyuan","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youqian","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiadong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeguang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1002\/jlb.6a1120-744r","article-title":"Use of integrated metabolomics, transcriptomics, and signal protein profile to characterize the effector function and associated metabotype of polarized macrophage phenotypes","volume":"111","author":"Anders","year":"2022","journal-title":"J. Leukoc. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1089\/ars.2016.6849","article-title":"Monocytes and macrophages: a fresh look at functional and phenotypic diversity","volume":"25","author":"Asmis","year":"2016","journal-title":"Antioxid. Redox Signal"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e002319","DOI":"10.1136\/jitc-2020-002319","article-title":"p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition","volume":"9","author":"Baumann","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2248","DOI":"10.1021\/acs.jcim.0c01227","article-title":"Toward an understanding of pan-assay interference compounds and promiscuity: a structural perspective on binding modes","volume":"61","author":"Bolz","year":"2021","journal-title":"J. Chem. Inf. Model"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2338","DOI":"10.1016\/s0140-6736(17)31491-5","article-title":"Novel treatment strategies in rheumatoid arthritis","volume":"389","author":"Burmester","year":"2017","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e131355","DOI":"10.1172\/jci.insight.131355","article-title":"STAT6\/Arg1 promotes microglia\/macrophage efferocytosis and inflammation resolution in stroke mice","volume":"4","author":"Cai","year":"2019","journal-title":"JCI Insight"},{"key":"B7","doi-asserted-by":"publisher","first-page":"607328","DOI":"10.3389\/fimmu.2020.607328","article-title":"Macrophage plasticity in reproduction and environmental influences on their function","volume":"11","author":"Chambers","year":"2020","journal-title":"Front. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1016\/j.kint.2018.10.041","article-title":"M2 macrophages in kidney disease: biology, therapies, and perspectives","volume":"95","author":"Chen","year":"2019","journal-title":"Kidney Int."},{"key":"B9","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/s41423-019-0315-0","article-title":"Epigenetic regulation of macrophages: from homeostasis maintenance to host defense","volume":"17","author":"Chen","year":"2020","journal-title":"Cell Mol. Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"117838","DOI":"10.1016\/j.jep.2024.117838","article-title":"Traditional Chinese medicine in regulating macrophage polarization in immune response of inflammatory diseases","volume":"325","author":"Chen","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"101610","DOI":"10.1016\/j.mtbio.2025.101610","article-title":"Injectable sustainable andrographolide-releasing hydrogel for long-lasting alleviation of osteoarthritis and regulation of chondrocyte autophagy via PRKCA\/EGFR","volume":"31","author":"Chen","year":"2025","journal-title":"Mater Today Bio"},{"key":"B12","doi-asserted-by":"publisher","first-page":"111024","DOI":"10.1016\/j.intimp.2023.111024","article-title":"Berberine ameliorates collagen-induced arthritis in mice by restoring macrophage polarization via AMPK\/mTORC1 pathway switching glycolytic reprogramming","volume":"124","author":"Cheng","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1186\/s12967-023-04772-6","article-title":"The role of AMPK in macrophage metabolism, function and polarisation","volume":"21","author":"Cui","year":"2023","journal-title":"J. Transl. Med."},{"key":"B14","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":"B15","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1038\/s41584-025-01279-w","article-title":"Dynamic macrophage phenotypes in autoimmune and inflammatory rheumatic diseases","volume":"21","author":"Cutolo","year":"2025","journal-title":"Nat. Rev. Rheumatol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1007\/s10753-023-01855-w","article-title":"Bavachinin ameliorates rheumatoid arthritis inflammation via PPARG\/PI3K\/AKT signaling pathway","volume":"46","author":"Deng","year":"2023","journal-title":"Inflammation"},{"key":"B17","doi-asserted-by":"publisher","first-page":"113560","DOI":"10.1016\/j.intimp.2024.113560","article-title":"Sappanone A attenuates rheumatoid arthritis via inhibiting PI3K\/AKT\/NF-\u03baB and JAK2\/STAT3 signaling pathways in vivo and in vitro","volume":"143","author":"Deng","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"101037","DOI":"10.1016\/j.ajps.2025.101037","article-title":"Multifunctional Prussian blue nanoparticles loading with Xuetongsu for efficient rheumatoid arthritis therapy through targeting inflammatory macrophages and osteoclasts","volume":"20","author":"Deng","year":"2025","journal-title":"Asian J. Pharm. Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"683","DOI":"10.3389\/fimmu.2014.00683","article-title":"Ontogeny and polarization of macrophages in inflammation: blood monocytes versus tissue macrophages","volume":"5","author":"Dey","year":"2014","journal-title":"Front. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.smim.2015.09.001","article-title":"Contribution of metabolic reprogramming to macrophage plasticity and function","volume":"27","author":"El Kasmi","year":"2015","journal-title":"Semin. Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1016\/j.cell.2020.02.041","article-title":"Toll-like receptors and the control of immunity","volume":"180","author":"Fitzgerald","year":"2020","journal-title":"Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1516","DOI":"10.1136\/ard-2023-224482","article-title":"Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2)","volume":"82","author":"Fleischmann","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1038\/s41590-024-01804-1","article-title":"JAK-STAT signaling maintains homeostasis in T cells and macrophages","volume":"25","author":"Fortelny","year":"2024","journal-title":"Nat. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"153197","DOI":"10.1016\/j.phymed.2020.153197","article-title":"Ginsenoside Rb1 exerts anti-inflammatory effects in vitro and in vivo by modulating toll-like receptor 4 dimerization and NF-kB\/MAPKs signaling pathways","volume":"69","author":"Gao","year":"2020","journal-title":"Phytomedicine"},{"key":"B25","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1007\/s11427-020-1939-1","article-title":"Punicalagin ameliorates collagen-induced arthritis by downregulating M1 macrophage and pyroptosis via NF-\u03baB signaling pathway","volume":"65","author":"Ge","year":"2022","journal-title":"Sci. China Life Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"103214","DOI":"10.1016\/j.jaut.2024.103214","article-title":"PPARG-mediated autophagy activation alleviates inflammation in rheumatoid arthritis","volume":"146","author":"Geng","year":"2024","journal-title":"J. Autoimmun."},{"key":"B27","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.cbpa.2020.04.020","article-title":"Advances of epigenetic editing","volume":"57","author":"Gjaltema","year":"2020","journal-title":"Curr. Opin. Chem. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e32","DOI":"10.1056\/NEJMp2310178","article-title":"What is rheumatoid arthritis?","volume":"390","author":"Gravallese","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"6229","DOI":"10.1021\/acsnano.3c09528","article-title":"Cerium-Luteolin nanocomplexes in managing inflammation-related diseases by antioxidant and immunoregulation","volume":"18","author":"Gu","year":"2024","journal-title":"ACS Nano"},{"key":"B30","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41392-024-01757-9","article-title":"NF-\u03baB in biology and targeted therapy: new insights and translational implications","volume":"9","author":"Guo","year":"2024","journal-title":"Signal Transduct. Target Ther."},{"key":"B31","doi-asserted-by":"publisher","first-page":"107686","DOI":"10.1016\/j.phrs.2025.107686","article-title":"A sinomenine derivative alleviates bone destruction in collagen-induced arthritis mice by suppressing mitochondrial dysfunction and oxidative stress via the NRF2\/HO-1\/NQO1 signaling pathway","volume":"215","author":"Guo","year":"2025","journal-title":"Pharmacol. Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"22544","DOI":"10.18632\/aging.203567","article-title":"Glaucocalyxin B inhibits cartilage inflammatory injury in rheumatoid arthritis by regulating M1 polarization of synovial macrophages through NF-\u03baB pathway","volume":"13","author":"Han","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"B33","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/s12944-018-0797-2","article-title":"Baicalin reduces blood lipids and inflammation in patients with coronary artery disease and rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial","volume":"17","author":"Hang","year":"2018","journal-title":"Lipids Health Dis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"eadj1252","DOI":"10.1126\/sciadv.adj1252","article-title":"Loss of synovial tissue macrophage homeostasis precedes rheumatoid arthritis clinical onset","volume":"10","author":"Hanlon","year":"2024","journal-title":"Sci. Adv."},{"key":"B35","doi-asserted-by":"publisher","first-page":"109955","DOI":"10.1016\/j.celrep.2021.109955","article-title":"Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors","volume":"37","author":"He","year":"2021","journal-title":"Cell Rep."},{"key":"B36","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/nrm.2017.95","article-title":"AMPK: guardian of metabolism and mitochondrial homeostasis","volume":"19","author":"Herzig","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"109095","DOI":"10.1016\/j.intimp.2022.109095","article-title":"Advance in bone destruction participated by JAK\/STAT in rheumatoid arthritis and therapeutic effect of JAK\/STAT inhibitors","volume":"111","author":"Hu","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"107100","DOI":"10.1016\/j.phrs.2024.107100","article-title":"Novel nano-drug delivery system for natural products and their application","volume":"201","author":"Huang","year":"2024","journal-title":"Pharmacol. Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"116006","DOI":"10.1016\/j.biopha.2023.116006","article-title":"Isoliquiritigenin inhibits apoptosis and ameliorates oxidative stress in rheumatoid arthritis chondrocytes through the Nrf2\/HO-1-mediated pathway","volume":"170","author":"Hung","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"B40","doi-asserted-by":"publisher","first-page":"108250","DOI":"10.1016\/j.intimp.2021.108250","article-title":"Baicalin alleviates mycoplasma gallisepticum-induced oxidative stress and inflammation via modulating NLRP3 inflammasome-autophagy pathway","volume":"101","author":"Ishfaq","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/s41392-023-01499-0","article-title":"Metabolic reprogramming of proinflammatory macrophages by target delivered roburic acid effectively ameliorates rheumatoid arthritis symptoms","volume":"8","author":"Jia","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"B42","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1093\/intimm\/dxaa017","article-title":"The spectrum of macrophage activation by immunometabolism","volume":"32","author":"Kang","year":"2020","journal-title":"Int. Immunol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"11624","DOI":"10.1038\/ncomms11624","article-title":"Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription","volume":"7","author":"Kobayashi","year":"2016","journal-title":"Nat. Commun."},{"key":"B44","doi-asserted-by":"publisher","first-page":"648037","DOI":"10.3389\/fphar.2021.648037","article-title":"Evaluating the therapeutic mechanisms of selected active compounds in Cornus officinalis and Paeonia Lactiflora in rheumatoid arthritis via network pharmacology analysis","volume":"12","author":"Li","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1038\/s41401-022-00957-9","article-title":"PPAR-\u03b3 alleviates the inflammatory response in TNF-\u03b1-induced fibroblast-like synoviocytes by binding to p53 in rheumatoid arthritis","volume":"44","author":"Li","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1002\/ptr.8158","article-title":"Quercetin as a promising intervention for rat osteoarthritis by decreasing M1-polarized macrophages via blocking the TRPV1-mediated P2X7\/NLRP3 signaling pathway","volume":"38","author":"Li","year":"2024","journal-title":"Phytother. Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1634580","DOI":"10.3389\/fendo.2025.1634580","article-title":"From molecular mechanism to plant intervention: the bidirectional regulation of inflammation and oxidative stress in bone aging","volume":"16","author":"Li","year":"2025","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.identj.2024.07.1213","article-title":"Ginsenoside RB1 influences Macrophage-DPSC interactions in inflammatory conditions","volume":"75","author":"Li","year":"2025","journal-title":"Int. Dent. J."},{"key":"B49","doi-asserted-by":"publisher","first-page":"115802","DOI":"10.1016\/j.jep.2022.115802","article-title":"Wutou decoction attenuates the synovial inflammation of collagen-induced arthritis rats via regulating macrophage M1\/M2 type polarization","volume":"301","author":"Lin","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1038\/s41401-020-00535-x","article-title":"Tanshinone IIA prevents LPS-induced inflammatory responses in mice via inactivation of succinate dehydrogenase in macrophages","volume":"42","author":"Liu","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"B51","doi-asserted-by":"publisher","first-page":"e002548","DOI":"10.1136\/jitc-2021-002548","article-title":"S100A4 enhances protumor macrophage polarization by control of PPAR-\u03b3-dependent induction of fatty acid oxidation","volume":"9","author":"Liu S.","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.3724\/abbs.2024076","article-title":"Oxypeucedanin hydrate alleviates rheumatoid arthritis by inhibiting the TLR4-MD2\/NF-\u03baB\/MAPK signaling axis","volume":"56","author":"Liu","year":"2024","journal-title":"Acta Biochim. Biophys. Sin. (Shanghai)"},{"key":"B53","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13075-025-03481-3","article-title":"Suberosin attenuates rheumatoid arthritis by repolarizing macrophages and inhibiting synovitis via the JAK\/STAT signaling pathway","volume":"27","author":"Liu","year":"2025","journal-title":"Arthritis Res. Ther."},{"key":"B54","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1146\/annurev-pathmechdis-012418-012718","article-title":"Diversity, mechanisms, and significance of macrophage plasticity","volume":"15","author":"Locati","year":"2020","journal-title":"Annu. Rev. Pathol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.3389\/fimmu.2019.01140","article-title":"The role of monocytes and macrophages in autoimmune diseases: a comprehensive review","volume":"10","author":"Ma","year":"2019","journal-title":"Front. Immunol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1182\/blood.2023023417","article-title":"Inflammation-driven NF-\u03baB signaling represses ferroportin transcription in macrophages via HDAC1 and HDAC3","volume":"145","author":"Marques","year":"2025","journal-title":"Blood"},{"key":"B57","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1056\/NEJMra1004965","article-title":"The pathogenesis of rheumatoid arthritis","volume":"365","author":"McInnes","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"102593","DOI":"10.1016\/j.autrev.2020.102593","article-title":"Immunomodulatory therapeutic effects of curcumin in rheumatoid arthritis","volume":"19","author":"Mohammadian Haftcheshmeh","year":"2020","journal-title":"Autoimmun. Rev."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1457010","DOI":"10.3389\/fimmu.2024.1457010","article-title":"The Nrf2-HO-1 system and inflammaging","volume":"15","author":"O'Rourke","year":"2024","journal-title":"Front. Immunol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.3390\/nu9121306","article-title":"Resveratrol role in autoimmune Disease-A mini-review","volume":"9","author":"Oliveira","year":"2017","journal-title":"Nutrients"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.3389\/fimmu.2019.01084","article-title":"Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. alternatively activated macrophages","volume":"10","author":"Orecchioni","year":"2019","journal-title":"Front. Immunol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"523","DOI":"10.2147\/itt.S485670","article-title":"JAK-STAT signaling in autoimmunity and cancer","volume":"14","author":"Parveen","year":"2025","journal-title":"Immunotargets Ther."},{"key":"B63","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/s40265-013-0014-6","article-title":"Mitogen-activated protein kinases as therapeutic targets for rheumatoid arthritis","volume":"73","author":"Paunovic","year":"2013","journal-title":"Drugs"},{"key":"B64","doi-asserted-by":"publisher","first-page":"1972","DOI":"10.1111\/febs.14801","article-title":"IL-35 ameliorates collagen-induced arthritis by promoting TNF-\u03b1-induced apoptosis of synovial fibroblasts and stimulating M2 macrophages polarization","volume":"286","author":"Peng","year":"2019","journal-title":"Febs J."},{"key":"B65","doi-asserted-by":"publisher","first-page":"652771","DOI":"10.3389\/fimmu.2021.652771","article-title":"Metabolic control of autoimmunity and tissue inflammation in rheumatoid arthritis","volume":"12","author":"Qiu","year":"2021","journal-title":"Front. Immunol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.jaci.2024.09.020","article-title":"JAK-STAT signaling pathway, immunodeficiency, inflammation, immune dysregulation, and inborn errors of immunity","volume":"155","author":"Samra","year":"2025","journal-title":"J. Allergy Clin. Immunol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"1575","DOI":"10.15036\/arerugi.62.1575","article-title":"Physiological role and differentiation mechanism of various M2 macrophages","volume":"62","author":"Satoh","year":"2013","journal-title":"Japanese J. Allergol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"154667","DOI":"10.1016\/j.phymed.2023.154667","article-title":"Astragalus polysaccharide ameliorates vascular endothelial dysfunction by stimulating macrophage M2 polarization via potentiating Nrf2\/HO-1 signaling pathway","volume":"112","author":"Sha","year":"2023","journal-title":"Phytomedicine"},{"key":"B69","doi-asserted-by":"publisher","first-page":"6425","DOI":"10.1002\/jcp.26429","article-title":"Macrophage plasticity, polarization, and function in health and disease","volume":"233","author":"Shapouri-Moghaddam","year":"2018","journal-title":"J. Cell Physiol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"154339","DOI":"10.1016\/j.phymed.2022.154339","article-title":"Magnoflorine attenuates inflammatory responses in RA by regulating the PI3K\/Akt\/NF-\u03baB and Keap1-Nrf2\/HO-1 signalling pathways in vivo and in vitro","volume":"104","author":"Shen","year":"2022","journal-title":"Phytomedicine"},{"key":"B71","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1146\/annurev-immunol-101320-031555","article-title":"Functional hallmarks of healthy macrophage responses: their regulatory basis and disease relevance","volume":"40","author":"Sheu","year":"2022","journal-title":"Annu. Rev. Immunol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.semarthrit.2020.10.008","article-title":"The Jak\/STAT pathway: a focus on pain in rheumatoid arthritis","volume":"51","author":"Simon","year":"2021","journal-title":"Semin. Arthritis Rheum."},{"key":"B73","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s11926-018-0725-5","article-title":"Macrophages, wound healing, and fibrosis: recent insights","volume":"20","author":"Smigiel","year":"2018","journal-title":"Curr. Rheumatol. Rep."},{"key":"B74","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1001\/jama.2022.0786","article-title":"What is rheumatoid arthritis?","volume":"327","author":"Smith","year":"2022","journal-title":"Jama"},{"key":"B75","doi-asserted-by":"publisher","first-page":"2023","DOI":"10.1016\/s0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"B76","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1136\/ard-2022-223356","article-title":"EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update","volume":"82","author":"Smolen","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"B77","doi-asserted-by":"publisher","first-page":"111382","DOI":"10.1016\/j.biopha.2021.111382","article-title":"Artesunate attenuates bone erosion in rheumatoid arthritis by suppressing reactive oxygen species via activating p62\/Nrf2 signaling","volume":"137","author":"Su","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"B78","doi-asserted-by":"publisher","first-page":"773592","DOI":"10.3389\/fphar.2021.773592","article-title":"Euphorbia factor L2 ameliorates the progression of K\/BxN serum-induced arthritis by blocking TLR7 mediated IRAK4\/IKK\u03b2\/IRF5 and NF-kB signaling pathways","volume":"12","author":"Tang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B79","doi-asserted-by":"publisher","first-page":"100622","DOI":"10.1016\/j.mtbio.2023.100622","article-title":"Reversing inflammatory microenvironment by a single intra-articular injection of multi-stimulus responsive lipogel to relieve rheumatoid arthritis and promote joint repair","volume":"20","author":"Tao","year":"2023","journal-title":"Mater Today Bio"},{"key":"B80","doi-asserted-by":"publisher","first-page":"102397","DOI":"10.1016\/j.autrev.2019.102397","article-title":"Macrophage M1\/M2 polarization and rheumatoid arthritis: a systematic review","volume":"18","author":"Tardito","year":"2019","journal-title":"Autoimmun. Rev."},{"key":"B81","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2014.00001","article-title":"Emerging role of endosomal toll-like receptors in rheumatoid arthritis","volume":"5","author":"Thwaites","year":"2014","journal-title":"Front. Immunol."},{"key":"B82","doi-asserted-by":"publisher","first-page":"967193","DOI":"10.3389\/fimmu.2022.967193","article-title":"Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Immunol."},{"key":"B83","doi-asserted-by":"publisher","first-page":"803037","DOI":"10.3389\/fimmu.2021.803037","article-title":"Macrophage polarization and its role in liver disease","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Immunol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"1516609","DOI":"10.3389\/fphar.2024.1516609","article-title":"Resveratrol-driven macrophage polarization: unveiling mechanisms and therapeutic potential","volume":"15","author":"Wang","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"155139","DOI":"10.1016\/j.phymed.2023.155139","article-title":"Targeted intervention of natural medicinal active ingredients and traditional Chinese medicine on epigenetic modification: possible strategies for prevention and treatment of atherosclerosis","volume":"122","author":"Wang W.","year":"2024","journal-title":"Phytomedicine"},{"key":"B86","doi-asserted-by":"publisher","first-page":"1613679","DOI":"10.3389\/fphar.2025.1613679","article-title":"Research progress in treatment of rheumatoid arthritis with sinomenine and related formulations based on different administration routes","volume":"16","author":"Wang W.","year":"2025","journal-title":"Front. Pharmacol."},{"key":"B87","doi-asserted-by":"publisher","first-page":"102643","DOI":"10.1016\/j.arr.2024.102643","article-title":"The role and mechanism of triptolide, a potential new DMARD, in the treatment of rheumatoid arthritis","volume":"104","author":"Wang","year":"2025","journal-title":"Ageing Res. Rev."},{"key":"B88","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1182\/blood-2012-01-403386","article-title":"CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair","volume":"120","author":"Willenborg","year":"2012","journal-title":"Blood"},{"key":"B89","doi-asserted-by":"publisher","first-page":"1598022","DOI":"10.3389\/fphar.2025.1598022","article-title":"Macrophage polarization in disease therapy: insights from astragaloside IV and cycloastragenol","volume":"16","author":"Xiong","year":"2025","journal-title":"Front. Pharmacol."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1234563","DOI":"10.3389\/fendo.2023.1234563","article-title":"Aconine attenuates osteoclast-mediated bone resorption and ferroptosis to improve osteoporosis via inhibiting NF-\u03baB signaling","volume":"14","author":"Xue","year":"2023","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B91","doi-asserted-by":"publisher","first-page":"155311","DOI":"10.1016\/j.phymed.2023.155311","article-title":"Jolkinolide B ameliorates rheumatoid arthritis by regulating the JAK2\/STAT3 signaling pathway","volume":"124","author":"Yan","year":"2024","journal-title":"Phytomedicine"},{"key":"B92","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.intimp.2016.10.005","article-title":"Triptolide inhibits the migration and invasion of rheumatoid fibroblast-like synoviocytes by blocking the activation of the JNK MAPK pathway","volume":"41","author":"Yang","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"B93","doi-asserted-by":"publisher","first-page":"113058","DOI":"10.1016\/j.intimp.2024.113058","article-title":"Potential mechanisms of rheumatoid arthritis therapy: focus on macrophage polarization","volume":"142","author":"Yang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.ijcard.2017.07.085","article-title":"M2b macrophages reduce early reperfusion injury after myocardial ischemia in mice: a predominant role of inhibiting apoptosis via A20","volume":"245","author":"Yue","year":"2017","journal-title":"Int. J. Cardiol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1002\/ptr.7324","article-title":"Andrographolide: a review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches","volume":"36","author":"Zeng","year":"2022","journal-title":"Phytother. Res."},{"key":"B96","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.cell.2016.12.012","article-title":"30 years of NF-\u03baB: a blossoming of relevance to human pathobiology","volume":"168","author":"Zhang","year":"2017","journal-title":"Cell"},{"key":"B97","doi-asserted-by":"publisher","first-page":"107529","DOI":"10.1016\/j.intimp.2021.107529","article-title":"Loganin alleviates sepsis-induced acute lung injury by regulating macrophage polarization and inhibiting NLRP3 inflammasome activation","volume":"95","author":"Zhang","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"B98","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1002\/med.21762","article-title":"Tripterygium wilfordii: an inspiring resource for rheumatoid arthritis treatment","volume":"41","author":"Zhang","year":"2021","journal-title":"Med. Res. Rev."},{"key":"B99","doi-asserted-by":"publisher","first-page":"e983","DOI":"10.1002\/iid3.983","article-title":"Naringenin ameliorates collagen-induced arthritis through activating AMPK-mediated autophagy in macrophages","volume":"11","author":"Zhang","year":"2023","journal-title":"Immun. Inflamm. Dis."},{"key":"B100","doi-asserted-by":"publisher","first-page":"112953","DOI":"10.1016\/j.intimp.2024.112953","article-title":"A synergistic effect of triptolide and curcumin on rheumatoid arthritis by improving cell proliferation and inducing cell apoptosis via inhibition of the IL-17\/NF-\u03baB signaling pathway","volume":"142","author":"Zhang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"B101","doi-asserted-by":"publisher","first-page":"e14454","DOI":"10.1111\/cbdd.14454","article-title":"Asiatic acid inhibits rheumatoid arthritis fibroblast-like synoviocyte growth through the Nrf2\/HO-1\/NF-\u03baB signaling pathway","volume":"103","author":"Zhang L.","year":"2024","journal-title":"Chem. Biol. Drug Des."},{"key":"B102","doi-asserted-by":"publisher","first-page":"1243149","DOI":"10.3389\/fimmu.2023.1243149","article-title":"M2 macrophage polarization: a potential target in pain relief","volume":"14","author":"Zhao","year":"2023","journal-title":"Front. Immunol."},{"key":"B103","doi-asserted-by":"publisher","first-page":"1394108","DOI":"10.3389\/fimmu.2024.1394108","article-title":"Macrophage polarization in rheumatoid arthritis: signaling pathways, metabolic reprogramming, and crosstalk with synovial fibroblasts","volume":"15","author":"Zheng","year":"2024","journal-title":"Front. Immunol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1186\/s12951-024-02822-9","article-title":"Macrophage membrane-camouflaged biomimetic nanoparticles for rheumatoid arthritis treatment via modulating macrophage polarization","volume":"22","author":"Zhou","year":"2024","journal-title":"J. Nanobiotechnology"},{"key":"B105","doi-asserted-by":"publisher","first-page":"118888","DOI":"10.1016\/j.jep.2024.118888","article-title":"Exploring the liver toxicity mechanism of Tripterygium wilfordii extract based on metabolomics, network pharmacological analysis and experimental validation","volume":"337","author":"Zhou","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"B106","doi-asserted-by":"publisher","first-page":"3417","DOI":"10.1002\/ptr.8217","article-title":"Luteolin: a promising multifunctional natural flavonoid for human diseases","volume":"38","author":"Zhu","year":"2024","journal-title":"Phytother. Res."},{"key":"B107","doi-asserted-by":"publisher","first-page":"114618","DOI":"10.1016\/j.colsurfb.2025.114618","article-title":"PEGylated retinoate prodrug self-assembled nanomicelles loaded with triptolide for targeting treatment of rheumatoid arthritis and side effect attenuation","volume":"251","author":"Zhu","year":"2025","journal-title":"Colloids Surf. B Biointerfaces"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1651763\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T05:29:45Z","timestamp":1760678985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1651763\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,17]]},"references-count":107,"alternative-id":["10.3389\/fphar.2025.1651763"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1651763","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,17]]},"article-number":"1651763"}}