{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T17:03:49Z","timestamp":1792343029072,"version":"4.4.0"},"reference-count":50,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Postdoctoral Start-up Fund of Tongji Hospital, Huazhong University of Science and Technology","award":["23-2RSC09039-31"],"award-info":[{"award-number":["23-2RSC09039-31"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Osteoarthritis (OA) is a prevalent degenerative disease globally, characterized by cartilage degradation and joint dysfunction. Current treatments are insufficient for halting OA progression. Irigenin (IRI), a flavonoid extracted from natural plants with anti-inflammatory and antioxidant properties, has demonstrated potential in mitigating inflammation and oxidative stress in various diseases; however, its effects on OA remain unexplored. This study aims to evaluate the therapeutic effects of IRI on OA through in vivo and in vitro experiments and to elucidate the underlying molecular mechanisms. Methods: In vitro, chondrocytes were exposed to hydrogen peroxide (H2O2) to induce an oxidative stress environment and were then treated with IRI. Western blotting, RT-qPCR, immunofluorescence staining assays, flow cytometry, and apoptosis assays were employed to assess the effects of IRI on chondrocyte matrix homeostasis, inflammatory response, and apoptosis. In vivo, an OA rat model was treated with regular IRI injections, and therapeutic effects were evaluated using micro-CT, histological staining, and immunohistochemistry assays. Results: IRI treatment restored matrix homeostasis in chondrocytes and effectively suppressed H2O2-induced inflammation and apoptosis. Subsequent studies further revealed that IRI exerts its therapeutic effects by activating the Nrf2\/HO-1 pathway. Inhibition of Nrf2 expression in chondrocytes partially blocked the anti-inflammatory and antioxidant effects of IRI. In the OA rat model, regular IRI injections effectively ameliorated cartilage degeneration. Conclusions: This study identifies IRI as a promising strategy for OA treatment by modulating inflammation and apoptosis through the Nrf2\/HO-1 pathway.<\/jats:p>","DOI":"10.3390\/ph17101268","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T04:05:46Z","timestamp":1727323546000},"page":"1268","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Anti-Inflammatory and Antioxidant Effects of Irigenen Alleviate Osteoarthritis Progression through Nrf2\/HO-1 Pathway"],"prefix":"10.3390","volume":"17","author":[{"given":"Xuan","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaohong","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1016\/S0140-6736(20)32230-3","article-title":"Osteoarthritis in 2020 and beyond: A Lancet Commission","volume":"396","author":"Hunter","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41586-023-06888-7","article-title":"Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis","volume":"625","author":"Fu","year":"2024","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1001\/jama.2020.22171","article-title":"Diagnosis and Treatment of Hip and Knee Osteoarthritis: A Review","volume":"325","author":"Katz","year":"2021","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101249","DOI":"10.1016\/j.arr.2020.101249","article-title":"The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis","volume":"66","author":"Zheng","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/s41584-022-00749-9","article-title":"Synovial inflammation in osteoarthritis progression","volume":"18","author":"Coras","year":"2022","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eabo5284","DOI":"10.1126\/sciadv.abo5284","article-title":"Tolerogenic nanoparticles induce type II collagen-specific regulatory T cells and ameliorate osteoarthritis","volume":"8","author":"Sohn","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1016\/S0140-6736(24)00475-6","article-title":"Dual-targeted disease-modifying therapies for osteoarthritis","volume":"403","author":"Zheng","year":"2024","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1007\/BF02976631","article-title":"Isoflavonoids from the rhizomes of Belamcanda chinensis and their effects on aldose reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues","volume":"25","author":"Jung","year":"2002","journal-title":"Arch. Pharm. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Mykhailenko, O., Petrikaite, V., Korinek, M., Chang, F.R., El-Shazly, M., Yen, C.H., Bezruk, I., Chen, B.H., Hsieh, C.F., and Lytkin, D. (2021). Pharmacological Potential and Chemical Composition of Crocus sativus Leaf Extracts. Molecules, 27.","DOI":"10.3390\/molecules27010010"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mykhailenko, O., Korinek, M., Ivanauskas, L., Bezruk, I., Myhal, A., Petrikait\u0117, V., El-Shazly, M., Lin, G.H., Lin, C.Y., and Yen, C.H. (2020). Qualitative and Quantitative Analysis of Ukrainian Iris Species: A Fresh Look on Their Antioxidant Content and Biological Activities. Molecules, 25.","DOI":"10.3390\/molecules25194588"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Guo, L., Zheng, X., Wang, E., Jia, X., Wang, G., and Wen, J. (2020). Irigenin treatment alleviates doxorubicin (DOX)-induced cardiotoxicity by suppressing apoptosis, inflammation and oxidative stress via the increase of miR-425. Biomed. Pharmacother., 125.","DOI":"10.1016\/j.biopha.2019.109784"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9603271231155098","DOI":"10.1177\/09603271231155098","article-title":"Irigenin attenuates lipopolysaccharide-induced acute lung injury by inactivating the mitogen-activated protein kinase (MAPK) signaling pathway","volume":"42","author":"Liu","year":"2023","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1002\/ddr.21802","article-title":"Irigenin alleviates angiotensin II-induced oxidative stress and apoptosis in HUVEC cells by activating Nrf2 pathway","volume":"82","author":"Zhang","year":"2021","journal-title":"Drug Dev. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1002\/ptr.6926","article-title":"Protective effects of irigenin against 1-methyl-4-phenylpyridinium-induced neurotoxicity through regulating the Keap1\/Nrf2 pathway","volume":"35","author":"Guo","year":"2021","journal-title":"Phytother. Res. PTR"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Vahidinia, Z., Azami Tameh, A., Barati, S., Izadpanah, M., and Seyed Hosseini, E. (2024). Nrf2 activation: A key mechanism in stem cell exosomes-mediated therapies. Cell. Mol. Biol. Lett., 29.","DOI":"10.1186\/s11658-024-00551-3"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.freeradbiomed.2019.12.007","article-title":"Relevance of Nrf2 and heme oxygenase-1 in articular diseases","volume":"157","author":"Alcaraz","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101756","DOI":"10.1016\/j.arr.2022.101756","article-title":"Role of Nrf2 in aging, Alzheimer\u2019s and other neurodegenerative diseases","volume":"82","author":"George","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11580","DOI":"10.1158\/0008-5472.CAN-06-3562","article-title":"Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis","volume":"66","author":"Khor","year":"2006","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.molmed.2023.07.008","article-title":"The NRF2\/Keap1 pathway as a therapeutic target in inflammatory bowel disease","volume":"29","author":"Geertsema","year":"2023","journal-title":"Trends Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.arr.2015.12.005","article-title":"Nrf2 signaling and redox homeostasis in the aging heart: A potential target to prevent cardiovascular diseases?","volume":"26","author":"Zazueta","year":"2016","journal-title":"Ageing Res. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.joca.2023.05.004","article-title":"Age and oxidative stress regulate Nrf2 homeostasis in human articular chondrocytes","volume":"31","author":"Taylor","year":"2023","journal-title":"Osteoarthr. Cartil."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.freeradbiomed.2018.01.013","article-title":"Nrf2\/ARE pathway attenuates oxidative and apoptotic response in human osteoarthritis chondrocytes by activating ERK1\/2\/ELK1-P70S6K-P90RSK signaling axis","volume":"116","author":"Khan","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.freeradbiomed.2017.02.041","article-title":"Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS\/ERK\/Nrf2 signaling pathways in human Osteoarthritis chondrocytes","volume":"106","author":"Khan","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1038\/s41401-021-00782-6","article-title":"CDDO-Im ameliorates osteoarthritis and inhibits chondrocyte apoptosis in mice via enhancing Nrf2-dependent autophagy","volume":"43","author":"Dong","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.freeradbiomed.2020.01.185","article-title":"Natural ingredients-derived antioxidants attenuate H2O2-induced oxidative stress and have chondroprotective effects on human osteoarthritic chondrocytes via Keap1\/Nrf2 pathway","volume":"152","author":"Yang","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"154330","DOI":"10.1016\/j.phymed.2022.154330","article-title":"Naringenin protects against iron overload-induced osteoarthritis by suppressing oxidative stress","volume":"105","author":"Pan","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ma, T., Jia, L., Zhao, J., Lv, L., Yu, Y., Ruan, H., Song, X., Chen, H., Li, X., and Zhang, J. (2022). Ginkgolide C slows the progression of osteoarthritis by activating Nrf2\/HO-1 and blocking the NF-\u03baB pathway. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1027553"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"108864","DOI":"10.1016\/j.intimp.2022.108864","article-title":"Asiaticoside ameliorates osteoarthritis progression through activation of Nrf2\/HO-1 and inhibition of the NF-\u03baB pathway","volume":"108","author":"Luo","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhang, G., Liao, Y., Yang, H., Tao, J., Ma, L., and Zuo, X. (2021). Irigenin reduces the expression of caspase-3 and matrix metalloproteinases, thus suppressing apoptosis and extracellular matrix degradation in TNF-\u03b1-stimulated nucleus pulposus cells. Chem. Biol. Interact., 349.","DOI":"10.1016\/j.cbi.2021.109681"},{"key":"ref_30","first-page":"236","article-title":"Quercetin-3-O-\u03b2-D-glucuronide attenuates osteoarthritis by inhibiting cartilage extracellular matrix degradation and inflammation","volume":"45","author":"Mao","year":"2024","journal-title":"J. Orthop. Transl."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.joca.2020.11.006","article-title":"Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2\/NF-\u03baB axis","volume":"29","author":"Shao","year":"2021","journal-title":"Osteoarthr. Cartil."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3214","DOI":"10.1021\/acschembio.6b00651","article-title":"Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors","volume":"11","author":"Singh","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1016\/j.lfs.2005.09.041","article-title":"Inhibitory effects of Irigenin from the rhizomes of Belamcanda chinensis on nitric oxide and prostaglandin E2 production in murine macrophage RAW 264.7 cells","volume":"78","author":"Ahn","year":"2006","journal-title":"Life Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nrrheum.2016.136","article-title":"Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis","volume":"12","author":"Robinson","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/j.joca.2023.06.005","article-title":"Fundamentals of osteoarthritis: Inflammatory mediators in osteoarthritis","volume":"31","author":"Monteagudo","year":"2023","journal-title":"Osteoarthr. Cartil."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.freeradbiomed.2009.12.022","article-title":"Reactive oxygen species, cellular redox systems, and apoptosis","volume":"48","author":"Circu","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1111\/jpi.12362","article-title":"Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin","volume":"61","author":"Hosseinzadeh","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"eabl6449","DOI":"10.1126\/sciadv.abl6449","article-title":"Injectable hydrogel microspheres with self-renewable hydration layers alleviate osteoarthritis","volume":"8","author":"Lei","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3735","DOI":"10.2147\/DDDT.S314767","article-title":"Bardoxolone-Methyl Prevents Oxidative Stress-Mediated Apoptosis and Extracellular Matrix Degradation In Vitro and Alleviates Osteoarthritis In Vivo","volume":"15","author":"Pang","year":"2021","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Busa, P., Lee, S.O., Huang, N., Kuthati, Y., and Wong, C.S. (2022). Carnosine Alleviates Knee Osteoarthritis and Promotes Synoviocyte Protection via Activating the Nrf2\/HO-1 Signaling Pathway: An In-Vivo and In-Vitro Study. Antioxidants, 11.","DOI":"10.3390\/antiox11061209"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"He, Q., Yang, J., Pan, Z., Zhang, G., Chen, B., Li, S., Xiao, J., Tan, F., Wang, Z., and Chen, P. (2023). Biochanin A protects against iron overload associated knee osteoarthritis via regulating iron levels and NRF2\/System xc-\/GPX4 axis. Biomed. Pharmacother., 157.","DOI":"10.1016\/j.biopha.2022.113915"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Luo, J., Wang, J., Zhang, J., Sang, A., Ye, X., Cheng, Z., and Li, X. (2022). Nrf2 Deficiency Exacerbated CLP-Induced Pulmonary Injury and Inflammation through Autophagy- and NF-\u03baB\/PPAR\u03b3-Mediated Macrophage Polarization. Cells, 11.","DOI":"10.3390\/cells11233927"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jaut.2018.07.005","article-title":"Nrf2-mediated metabolic reprogramming of tolerogenic dendritic cells is protective against aplastic anemia","volume":"94","author":"Wei","year":"2018","journal-title":"J. Autoimmun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e2305563","DOI":"10.1002\/advs.202305563","article-title":"VDR Activation Attenuates Renal Tubular Epithelial Cell Ferroptosis by Regulating Nrf2\/HO-1 Signaling Pathway in Diabetic Nephropathy","volume":"11","author":"Wang","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e14456","DOI":"10.1111\/cns.14456","article-title":"Neutral polysaccharide from Gastrodia elata alleviates cerebral ischemia-reperfusion injury by inhibiting ferroptosis-mediated neuroinflammation via the NRF2\/HO-1 signaling pathway","volume":"30","author":"Zhang","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1111\/bph.15961","article-title":"Icariside II preconditioning evokes robust neuroprotection against ischaemic stroke, by targeting Nrf2 and the OXPHOS\/NF-\u03baB\/ferroptosis pathway","volume":"180","author":"Gao","year":"2023","journal-title":"Br. J. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Lee, J.J., Ng, S.C., Hsu, J.Y., Liu, H., Chen, C.J., Huang, C.Y., and Kuo, W.W. (2022). Galangin Reverses H2O2-Induced Dermal Fibroblast Senescence via SIRT1-PGC-1\u03b1\/Nrf2 Signaling. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031387"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.joca.2022.01.009","article-title":"Rhoifolin ameliorates osteoarthritis via the Nrf2\/NF-\u03baB axis: In vitro and in vivo experiments","volume":"30","author":"Chen","year":"2022","journal-title":"Osteoarthr. Cartil."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.freeradbiomed.2023.01.006","article-title":"Baicalein limits osteoarthritis development by inhibiting chondrocyte ferroptosis","volume":"196","author":"Wan","year":"2023","journal-title":"Free Radic. Biol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e2204438","DOI":"10.1002\/advs.202204438","article-title":"DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination","volume":"10","author":"Wang","year":"2023","journal-title":"Adv. Sci."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/10\/1268\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:03:26Z","timestamp":1760112206000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/10\/1268"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,26]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ph17101268"],"URL":"https:\/\/doi.org\/10.3390\/ph17101268","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,26]]}}}