{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T17:14:10Z","timestamp":1783358050382,"version":"3.54.6"},"reference-count":96,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"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":["82060873"],"award-info":[{"award-number":["82060873"]}],"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":["82174412"],"award-info":[{"award-number":["82174412"]}],"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":["82374491"],"award-info":[{"award-number":["82374491"]}],"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":["82160911"],"award-info":[{"award-number":["82160911"]}],"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:p>\n                    Osteoarthritis (OA) is a prevalent degenerative joint disease with multifactorial pathogenesis and no cure. Traditional Chinese Medicine (TCM) is widely used in OA management, and accumulating research suggests that bioactive metabolites (formerly termed active components) from TCM botanical drugs can modulate key pathological processes in OA. Traditional Chinese medicine has an important role in OA management owing to its relatively low incidence of adverse effects, affordability, and multi-target therapeutic actions. In this review, we systematically searched PubMed and Web of Science (2010\u20132025) for studies on TCM-derived metabolites in OA using keywords such as \u201costeoarthritis,\u201d \u201cTraditional Chinese Medicine,\u201d \u201cactive constituent,\u201d and \u201cmechanism.\u201d Relevant\n                    <jats:italic>in vitro<\/jats:italic>\n                    ,\n                    <jats:italic>in vivo<\/jats:italic>\n                    , and clinical studies were included based on predefined criteria. We critically evaluated the pharmacological rigor of these studies (models, controls, and translational relevance) and synthesized their findings. Numerous TCM metabolites including flavonoids, polyphenols, saponins, alkaloids, and polysaccharides exhibit chondroprotective effects in preclinical OA models by regulating inflammatory mediators, oxidative stress, cartilage matrix degradation, chondrocyte apoptosis senescence, macrophage polarization, ferroptosis, and gut microbiota composition. These compounds act through pathways such as NF-\u03baB, PI3K\/Akt\/mTOR, and Wnt\/\u03b2-catenin, reflecting multi-target mechanisms. Notably, compounds like quercetin and resveratrol are ubiquitous plant metabolites (not unique to TCM) and illustrate structure activity relationships. While promising, most evidence is confined to cell and animal studies with limited clinical validation. We discuss the strengths and limitations of current studies and identify priorities for future research, such as improving bioavailability and conducting high-quality clinical trials. In conclusion, TCM-derived metabolites show potential as multi-target agents for OA, but rigorous clinical studies and advanced delivery strategies are needed to translate these mechanistic insights into effective therapies.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1786112","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:43:45Z","timestamp":1774248225000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Mechanisms of active metabolites from traditional Chinese medicine in osteoarthritis: a critical review"],"prefix":"10.3389","volume":"17","author":[{"given":"Hui","family":"Li","sequence":"first","affiliation":[{"name":"Affiliated Hospital of Gansu University of Traditional Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongli","family":"Zhao","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Gansu University of Traditional Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Qi","sequence":"additional","affiliation":[{"name":"Gansu University of Traditional Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Gansu University of Traditional Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilong","family":"Ma","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Gansu University of Traditional Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingwen","family":"Xie","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Gansu University of Traditional Chinese Medicine","place":["Lanzhou, China"]},{"name":"Gansu University of Traditional Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Li","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Gansu University of Traditional Chinese Medicine","place":["Lanzhou, China"]},{"name":"Gansu University of Traditional Chinese Medicine","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.mcna.2019.10.007","article-title":"Osteoarthritis: pathology, diagnosis, and treatment options","volume":"104","author":"Abramoff","year":"2020","journal-title":"Med. Clin. North Am."},{"key":"B2","doi-asserted-by":"publisher","first-page":"110452","DOI":"10.1016\/j.biopha.2020.110452","article-title":"Oxidative stress and inflammation in osteoarthritis pathogenesis: role of polyphenols","volume":"129","author":"Ansari","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"B3","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1002\/jcb.24362","article-title":"Vertical inhibition of the PI3K\/Akt\/mTOR pathway for the treatment of osteoarthritis","volume":"114","author":"Chen","year":"2013","journal-title":"J. Cell Biochem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1007\/s00005-018-0518-6","article-title":"Baicalin attenuates joint pain and muscle dysfunction by inhibiting muscular oxidative stress in an experimental osteoarthritis rat model","volume":"66","author":"Chen","year":"2018","journal-title":"Arch. Immunol. Ther. Exp. (Warsz)."},{"key":"B5","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":"B6","doi-asserted-by":"publisher","first-page":"1826299","DOI":"10.1155\/2022\/1826299","article-title":"Network pharmacology-based strategy to investigate the mechanisms of Cibotium barometz in treating osteoarthritis","volume":"2022","author":"Chen","year":"","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1186\/s40001-022-00820-x","article-title":"Icariin alleviates osteoarthritis through PI3K\/Akt\/mTOR\/ULK1 signaling pathway","volume":"27","author":"Chen","year":"","journal-title":"Eur. J. Med. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2365","DOI":"10.3390\/ijms24032365","article-title":"Dendrobine alleviates cellular senescence and osteoarthritis via the ROS\/NF-\u03baB axis","volume":"24","author":"Chen","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"263","DOI":"10.3390\/nu9030263","article-title":"Chondroprotective effects of ginsenoside Rg1 in human osteoarthritis chondrocytes and a rat model of anterior cruciate ligament transection","volume":"9","author":"Cheng","year":"2017","journal-title":"Nutrients"},{"key":"B10","doi-asserted-by":"publisher","first-page":"930511","DOI":"10.3389\/fimmu.2022.930511","article-title":"Lactobacillus (LA-1) and butyrate inhibit osteoarthritis by controlling autophagy and inflammatory cell death of chondrocytes","volume":"13","author":"Cho","year":"2022","journal-title":"Front. Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"4063","DOI":"10.3390\/cimb46050251","article-title":"Osteoarthritis: insights into diagnosis, pathophysiology, therapeutic avenues, and the potential of natural extracts","volume":"46","author":"Coppola","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/bs.pmbts.2017.02.005","article-title":"Biochemical and biological attributes of matrix metalloproteinases","volume":"147","author":"Cui","year":"2017","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"13254","DOI":"10.1038\/ncomms13254","article-title":"A systems study reveals concurrent activation of AMPK and mTOR by amino acids","volume":"7","author":"Dalle Pezze","year":"2016","journal-title":"Nat. Commun."},{"key":"B14","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1007\/164_2021_525","article-title":"WNT signalling in osteoarthritis and its pharmacological targeting","volume":"269","author":"De Palma","year":"2021","journal-title":"Handb. Exp. Pharmacol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"4564","DOI":"10.1111\/bph.14048","article-title":"Assembly and architecture of the Wnt\/\u03b2-catenin signalosome at the membrane","volume":"174","author":"DeBruine","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/nrrheum.2015.145","article-title":"Osteoarthritis: autophagy prevents age-related OA","volume":"11","author":"Duarte","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1186\/s12891-020-03785-2","article-title":"Celebrating 20 years of open access publishing at BMC musculoskeletal disorders","volume":"21","author":"Fitzpatrick","year":"2020","journal-title":"BMC Musculoskelet. Disord."},{"key":"B18","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13018-024-05055-6","article-title":"Mechanisms of chondrocyte cell death in osteoarthritis: implications for disease progression and treatment","volume":"19","author":"Guan","year":"2024","journal-title":"J. Orthop. Surg. Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.clim.2012.12.011","article-title":"Immunopathogenesis of osteoarthritis","volume":"146","author":"Haseeb","year":"2013","journal-title":"Clin. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1302\/2046-3758.115.BJR-2021-0334.R1","article-title":"The role of AGEs in pathogenesis of cartilage destruction in osteoarthritis","volume":"11","author":"He","year":"2022","journal-title":"Bone Jt. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"113915","DOI":"10.1016\/j.biopha.2022.113915","article-title":"Biochanin A protects against iron overload associated knee osteoarthritis via regulating iron levels and NRF2\/System xc-\/GPX4 axis","volume":"157","author":"He","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"B22","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1002\/art.41486","article-title":"Synergistic roles of macrophages and neutrophils in osteoarthritis progression","volume":"73","author":"Hsueh","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/s41413-025-00470-9","article-title":"Cytosolic phospholipase A2 as a therapeutic target for degenerative joint diseases","volume":"13","author":"Huang","year":"2025","journal-title":"Bone Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"156141","DOI":"10.1016\/j.phymed.2024.156141","article-title":"Cannabiorcol as a novel inhibitor of the p38\/MSK-1\/NF-\u03baB signaling pathway, reducing matrix metalloproteinases in osteoarthritis","volume":"135","author":"Jeon","year":"2024","journal-title":"Phytomedicine"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3946320241271724","DOI":"10.1177\/03946320241271724","article-title":"Protocatechuic aldehyde attenuates chondrocyte senescence via the regulation of PTEN-induced kinase 1\/Parkin-mediated mitochondrial autophagy","volume":"38","author":"Jie","year":"2024","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"157563","DOI":"10.1016\/j.phymed.2025.157563","article-title":"Sclareol alleviates synovial inflammation in knee osteoarthritis by regulating sphingolipid metabolism along the gut-bone axis","volume":"149","author":"Jie","year":"2025","journal-title":"Phytomedicine"},{"key":"B27","doi-asserted-by":"publisher","first-page":"83","DOI":"10.3892\/mmr.2020.11722","article-title":"Scutellarin regulates osteoarthritis in vitro by inhibiting the PI3K\/AKT\/mTOR signaling pathway","volume":"23","author":"Ju","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"192415","DOI":"10.1155\/2015\/192415","article-title":"Recognition of immune response for the early diagnosis and treatment of osteoarthritis","volume":"2015","author":"Kandahari","year":"2015","journal-title":"J. Immunol. Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"117033","DOI":"10.1016\/j.taap.2024.117033","article-title":"Gallic acid ameliorates synovial inflammation and fibrosis by regulating the intestinal flora and its metabolites","volume":"490","author":"Kang","year":"2024","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.3390\/ijms26051901","article-title":"Potential chondroprotective effect of Artemisia annua L. water extract on SW1353 cell","volume":"26","author":"Kim","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"28620","DOI":"10.1074\/jbc.M113.452169","article-title":"Transcriptional induction of ADAMTS5 protein by nuclear factor-\u03baB (NF-\u03baB) family member RelA\/p65 in chondrocytes during osteoarthritis development","volume":"288","author":"Kobayashi","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"133137","DOI":"10.1016\/j.ijbiomac.2024.133137","article-title":"Polygonatum sibiricum polysaccharides protect against knee osteoarthritis by inhibiting the TLR2\/NF-\u03baB signaling pathway in vivo and in vitro","volume":"274","author":"Kuang","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"91","DOI":"10.2174\/157339711402180706144757","article-title":"Osteoarthritis - current insights in pathogenesis, diagnosis and treatment","volume":"14","author":"Lambova","year":"2018","journal-title":"Curr. Rheumatol. Rev."},{"key":"B34","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1136\/annrheumdis-2016-209757","article-title":"Systemic inhibition of IL-6\/Stat3 signalling protects against experimental osteoarthritis","volume":"76","author":"Latourte","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"B35","doi-asserted-by":"publisher","first-page":"9150","DOI":"10.1021\/acs.jafc.3c09749","article-title":"Pterostilbene protects against osteoarthritis through NLRP3 inflammasome inactivation and improves gut microbiota as evidenced by in vivo and in vitro studies","volume":"72","author":"Lee","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.freeradbiomed.2018.09.025","article-title":"Redox and NF-\u03baB signaling in osteoarthritis","volume":"132","author":"Lepetsos","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.26355\/eurrev_202102_24821","article-title":"MicroRNAs target on cartilage extracellular matrix degradation of knee osteoarthritis","volume":"25","author":"Li","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"5190986","DOI":"10.1155\/2017\/5190986","article-title":"Insights into the action mechanisms of traditional Chinese medicine in osteoarthritis","volume":"2017","author":"Li","year":"2017","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.bbrc.2019.12.065","article-title":"Chondrocytes-derived exosomal miR-8485 regulated the Wnt\/\u03b2-catenin pathways to promote chondrogenic differentiation of BMSCs","volume":"523","author":"Li","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B40","doi-asserted-by":"publisher","first-page":"579323","DOI":"10.3389\/fcimb.2021.579323","article-title":"The role of intestinal flora in the regulation of bone homeostasis","volume":"11","author":"Li","year":"2021","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.actbio.2021.12.006","article-title":"The immune microenvironment in cartilage injury and repair","volume":"140","author":"Li","year":"2022","journal-title":"Acta Biomater."},{"key":"B42","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/s41413-025-00448-7","article-title":"Cellular senescence and other age-related mechanisms in skeletal diseases","volume":"13","author":"Li","year":"2025","journal-title":"Bone Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"860","DOI":"10.3390\/biomedicines10040860","article-title":"Gut microbiota ecosystem governance of host inflammation, mitochondrial respiration and skeletal homeostasis","volume":"10","author":"Lian","year":"2022","journal-title":"Biomedicines"},{"key":"B44","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1186\/s13018-024-05075-2","article-title":"Amentoflavone maintaining extracellular matrix homeostasis and inhibiting subchondral bone loss in osteoarthritis by inhibiting ERK, JNK and NF-\u03baB signaling pathways","volume":"19","author":"Liang","year":"2024","journal-title":"J. Orthop. Surg. Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41392-021-00762-6","article-title":"Wnt\/\u03b2-catenin signalling: function, biological mechanisms, and therapeutic opportunities","volume":"7","author":"Liu","year":"2022","journal-title":"Signal Transduct. Target Ther."},{"key":"B46","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1136\/bmjebm-2023-112626","article-title":"Clinical effect and contributing factors of acupuncture for knee osteoarthritis: a systematic review and pairwise and exploratory network meta-analysis","volume":"29","author":"Liu","year":"","journal-title":"BMJ Evid. Based Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"155593","DOI":"10.1016\/j.phymed.2024.155593","article-title":"Cartilage protective and anti-edema effects of JTF in osteoarthritis via inhibiting NCOA4-HMGB1-driven ferroptosis and aquaporin dysregulation","volume":"129","author":"Liu","year":"","journal-title":"Phytomedicine"},{"key":"B48","doi-asserted-by":"publisher","first-page":"118446","DOI":"10.1016\/j.jep.2024.118446","article-title":"in vitro and in vivo studies of the therapeutic potential of Tinospora crispa extracts in osteoarthritis: targeting oxidation, inflammation, and chondroprotection","volume":"333","author":"Llamasares-Castillo","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1016\/j.biopha.2018.07.062","article-title":"Scoparone prevents IL-1\u03b2-induced inflammatory response in human osteoarthritis chondrocytes through the PI3K\/Akt\/NF-\u03baB pathway","volume":"106","author":"Lu","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"B50","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/s13075-021-02512-z","article-title":"Fargesin ameliorates osteoarthritis via macrophage reprogramming by downregulating MAPK and NF-\u03baB pathways","volume":"23","author":"Lu","year":"2021","journal-title":"Arthritis Res. Ther."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1060721","DOI":"10.3389\/fendo.2022.1060721","article-title":"Oroxin B alleviates osteoarthritis through anti-inflammation and inhibition of PI3K\/AKT\/mTOR signaling pathway and enhancement of autophagy","volume":"13","author":"Lu","year":"2022","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B52","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1186\/s13018-025-05785-1","article-title":"Quercetin-primed MSC exosomes synergistically attenuate osteoarthritis progression","volume":"20","author":"Lu","year":"2025","journal-title":"J. Orthop. Surg. Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"284873","DOI":"10.1155\/2013\/284873","article-title":"The role of changes in extracellular matrix of cartilage in the presence of inflammation on the pathology of osteoarthritis","volume":"2013","author":"Maldonado","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"B54","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1111\/nyas.13407","article-title":"Oxidative stress and chronic inflammation in osteoarthritis: can NRF2 counteract these partners in crime?","volume":"1401","author":"Marchev","year":"2017","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1002\/acr.23425","article-title":"Medical expenditures and earnings losses among US adults with arthritis in 2013","volume":"70","author":"Murphy","year":"2018","journal-title":"Arthritis Care Res. Hob."},{"key":"B56","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1111\/j.1474-9726.2012.00795.x","article-title":"A senescent cell bystander effect: senescence-induced senescence","volume":"11","author":"Nelson","year":"2012","journal-title":"Aging Cell"},{"key":"B57","doi-asserted-by":"publisher","first-page":"e218","DOI":"10.1111\/hae.12208","article-title":"Identification and expression of iron regulators in human synovium: evidence for upregulation in haemophilic arthropathy compared to rheumatoid arthritis, osteoarthritis, and healthy controls","volume":"19","author":"Nieuwenhuizen","year":"2013","journal-title":"Haemophilia"},{"key":"B58","doi-asserted-by":"publisher","first-page":"363","DOI":"10.3899\/jrheum.140382","article-title":"The role of innate immunity in osteoarthritis: when our first line of defense goes on the offensive","volume":"42","author":"Orlowsky","year":"2015","journal-title":"J. Rheumatol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.intimp.2017.08.010","article-title":"Alpha-mangostin protects rat articular chondrocytes against IL-1\u03b2-induced inflammation and slows the progression of osteoarthritis in a rat model","volume":"52","author":"Pan","year":"2017","journal-title":"Int. Immunopharmacol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1002\/art.43089","article-title":"Association of synovial innate immune exhaustion with worse pain in knee osteoarthritis","volume":"77","author":"Philpott","year":"2025","journal-title":"Arthritis Rheumatol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.arr.2017.07.004","article-title":"Aging and osteoarthritis: central role of the extracellular matrix","volume":"40","author":"Rahmati","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"B62","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/j.joca.2011.02.004","article-title":"Expression and function of the insulin receptor in normal and osteoarthritic human chondrocytes: modulation of anabolic gene expression, glucose transport and GLUT-1 content by insulin","volume":"19","author":"Rosa","year":"2011","journal-title":"Osteoarthr. Cartil."},{"key":"B63","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1038\/s41392-024-01969-z","article-title":"Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects","volume":"9","author":"Ru","year":"2024","journal-title":"Signal Transduct. Target Ther."},{"key":"B64","doi-asserted-by":"publisher","first-page":"110835","DOI":"10.1016\/j.cbi.2023.110835","article-title":"Ruscogenin attenuates cartilage destruction in osteoarthritis through suppressing chondrocyte ferroptosis via Nrf2\/SLC7A11\/GPX4 signaling pathway","volume":"388","author":"Ruan","year":"2024","journal-title":"Chem. Biol. Interact."},{"key":"B65","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/978-981-13-3681-2-6","article-title":"Ageing and osteoarthritis","volume":"91","author":"Sacitharan","year":"2019","journal-title":"Subcell. Biochem."},{"key":"B66","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1080\/03008207.2016.1208655","article-title":"Inflammation and epigenetic regulation in osteoarthritis","volume":"58","author":"Shen","year":"2017","journal-title":"Connect. Tissue Res."},{"key":"B67","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.joca.2020.02.027","article-title":"The PI3K\/AKT\/mTOR signaling pathway in osteoarthritis: a narrative review","volume":"28","author":"Sun","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"B68","doi-asserted-by":"publisher","first-page":"1168818","DOI":"10.3389\/fimmu.2023.1168818","article-title":"The immune role of the intestinal microbiome in knee osteoarthritis: a review of the possible mechanisms and therapies","volume":"14","author":"Sun","year":"2023","journal-title":"Front. Immunol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"113359","DOI":"10.1016\/j.intimp.2024.113359","article-title":"Wedelolactone alleviates inflammation and cartilage degeneration by suppressing the NF-\u03baB signaling pathway in osteoarthritis","volume":"143","author":"Sun","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1007\/s10753-016-0309-3","article-title":"Tenuigenin prevents IL-1\u03b2-induced inflammation in human osteoarthritis chondrocytes by suppressing PI3K\/AKT\/NF-\u03baB signaling pathway","volume":"39","author":"Wang","year":"2016","journal-title":"Inflammation"},{"key":"B71","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jare.2022.01.004","article-title":"Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx","volume":"41","author":"Wang","year":"2022","journal-title":"J. Adv. Res."},{"key":"B72","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.3892\/ijmm.2014.1869","article-title":"Achyranthes bidentata polysaccharides activate the Wnt\/\u03b2-catenin signaling pathway to promote chondrocyte proliferation","volume":"34","author":"Weng","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"B73","doi-asserted-by":"publisher","first-page":"dev165902","DOI":"10.1242\/dev.165902","article-title":"Wnt signalling: conquering complexity","volume":"145","author":"Wiese","year":"2018","journal-title":"Development"},{"key":"B74","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.matbio.2014.08.009","article-title":"The structure and function of the pericellular matrix of articular cartilage","volume":"39","author":"Wilusz","year":"2014","journal-title":"Matrix Biol."},{"key":"B75","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1186\/1472-6882-14-444","article-title":"Protective effects of biochanin A on articular cartilage: in vitro and in vivo studies","volume":"14","author":"Wu","year":"2014","journal-title":"BMC Complement. Altern. Med."},{"key":"B76","doi-asserted-by":"publisher","first-page":"109136","DOI":"10.1016\/j.cbi.2020.109136","article-title":"Stachydrine attenuates IL-1\u03b2-induced inflammatory response in osteoarthritis chondrocytes through the NF-\u03baB signaling pathway","volume":"326","author":"Wu","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"B77","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1111\/cbdd.14101","article-title":"Ganoderic acid A improves osteoarthritis by regulating RANKL\/OPG ratio","volume":"100","author":"Wu","year":"2022","journal-title":"Chem. Biol. Drug Des."},{"key":"B78","doi-asserted-by":"publisher","first-page":"115111","DOI":"10.1016\/j.intimp.2025.115111","article-title":"Paeoniflorin mitigates iron overload-induced osteoarthritis by suppressing chondrocyte ferroptosis via the p53\/SLC7A11\/GPX4 pathway","volume":"162","author":"Wu","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"B79","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1007\/s00223-014-9917-9","article-title":"Osteoarthritis pathogenesis: a review of molecular mechanisms","volume":"95","author":"Xia","year":"2014","journal-title":"Calcif. Tissue Int."},{"key":"B80","doi-asserted-by":"publisher","first-page":"2621","DOI":"10.1080\/15548627.2023.2218764","article-title":"GPX4 in cell death, autophagy, and disease","volume":"19","author":"Xie","year":"2023","journal-title":"Autophagy"},{"key":"B81","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1093\/gerona\/glw154","article-title":"Transplanted senescent cells induce an osteoarthritis-like condition in mice","volume":"72","author":"Xu","year":"2017","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"B82","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1080\/03008207.2020.1778679","article-title":"Magnolin exhibits anti-inflammatory effects on chondrocytes via the NF-\u03baB pathway for attenuating anterior cruciate ligament transection-induced osteoarthritis","volume":"62","author":"Xu","year":"2021","journal-title":"Connect. Tissue Res."},{"key":"B83","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41392-023-01330-w","article-title":"Osteoarthritis: pathogenic signaling pathways and therapeutic targets","volume":"8","author":"Yao","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"B84","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1186\/s13018-020-01944-8","article-title":"Resveratrol alleviates the interleukin-1\u03b2-induced chondrocytes injury through the NF-\u03baB signaling pathway","volume":"15","author":"Yi","year":"2020","journal-title":"J. Orthop. Surg. Res."},{"key":"B85","doi-asserted-by":"publisher","first-page":"117569","DOI":"10.1016\/j.ecoenv.2024.117569","article-title":"Selenomethionine alleviates T-2 toxin-induced articular chondrocyte ferroptosis via the system Xc-\/GSH\/GPX4 axis","volume":"290","author":"Yu","year":"2025","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B86","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.intimp.2013.11.021","article-title":"Chondroprotective effects and multi-target mechanisms of icariin in IL-1 beta-induced human SW 1353 chondrosarcoma cells and a rat osteoarthritis model","volume":"18","author":"Zeng","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"B87","doi-asserted-by":"publisher","first-page":"2853","DOI":"10.3892\/mmr.2017.6312","article-title":"Icariin inhibits MMP-1, MMP-3 and MMP-13 expression through MAPK pathways in IL-1\u03b2-stimulated SW1353 chondrosarcoma cells","volume":"15","author":"Zeng","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"B88","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1136\/annrheumdis-2013-204599","article-title":"Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis","volume":"74","author":"Zhang","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"B89","doi-asserted-by":"publisher","first-page":"116512","DOI":"10.1016\/j.biopha.2024.116512","article-title":"GPX4, ferroptosis, and diseases","volume":"174","author":"Zhang","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"B90","doi-asserted-by":"publisher","first-page":"138","DOI":"10.3892\/mmr.2025.13502","article-title":"Salidroside ameliorates lipopolysaccharide-induced ferroptosis in chondrocytes via regulation of the sirt1\/foxo1 axis","volume":"31","author":"Zhang","year":"2025","journal-title":"Mol. Med. Rep."},{"key":"B91","doi-asserted-by":"publisher","first-page":"117493","DOI":"10.1016\/j.jep.2023.117493","article-title":"Efficacy and safety of curcumin therapy for knee osteoarthritis: a Bayesian network meta-analysis","volume":"321","author":"Zhao","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"B92","doi-asserted-by":"publisher","first-page":"2575","DOI":"10.1159\/000495926","article-title":"Artemisinin ameliorates osteoarthritis by inhibiting the Wnt\/\u03b2-Catenin signaling pathway","volume":"51","author":"Zhong","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"B93","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s11926-017-0679-z","article-title":"Wnt\/\u03b2-catenin signaling in osteoarthritis and in other forms of arthritis","volume":"19","author":"Zhou","year":"2017","journal-title":"Curr. Rheumatol. Rep."},{"key":"B94","doi-asserted-by":"publisher","first-page":"114323","DOI":"10.1016\/j.intimp.2025.114323","article-title":"Notopterol mitigates osteoarthritis progression and relieves pain in mice by inhibiting PI3K\/Akt\/GPX4-mediated ferroptosis","volume":"151","author":"Zhou","year":"","journal-title":"Int. Immunopharmacol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"e70407","DOI":"10.1002\/jbt.70407","article-title":"Pterostilbene improves apoptosis, inflammation, and autophagy of osteoarthritis chondrocytes through the Ras\/Raf\/MEK\/ERK pathway","volume":"39","author":"Zhou","year":"","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"755260","DOI":"10.3389\/fbioe.2022.755260","article-title":"Icariin-loaded hydrogel regulates bone marrow mesenchymal stem cell chondrogenic differentiation and promotes cartilage repair in osteoarthritis","volume":"10","author":"Zhu","year":"2022","journal-title":"Front. Bioeng. Biotechnol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1786112\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:43:46Z","timestamp":1774248226000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1786112\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,23]]},"references-count":96,"alternative-id":["10.3389\/fphar.2026.1786112"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1786112","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,23]]},"article-number":"1786112"}}