{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T12:58:43Z","timestamp":1791377923711,"version":"4.3.2"},"reference-count":48,"publisher":"PAGEPress Publications","issue":"4","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Histochem"],"abstract":"<jats:p>Sinensetin (SIN) is a natural flavonoid with potential anti\u2011inflammatory effects. This study investigated whether SIN ameliorates osteoarthritis (OA) and explored its underlying mechanisms. In vitro, SIN (0.05-1\u202f\u03bcg\/mL) protected human OA chondrocytes from IL\u20111\u03b2\u2011induced viability loss. Transcriptome sequencing and molecular docking identified SERPINA3 as a candidate target of SIN. SIN reduced the expression of NLRP3, GSDMD, and ASC, inhibited pyroptotic morphology, decreased TUNEL\u2011positive cells and LDH release, and lowered IL\u20111\u03b2 and IL\u201118 secretion in IL\u20111\u03b2\u2011treated chondrocytes. Knockdown of SERPINA3 reversed these effects, suggesting that SIN acts through SERPINA3 to inhibit the NLRP3 inflammasome. In a rat DMM\u2011induced OA model, SIN (20\u202fmg\/kg\/day for 6 weeks) alleviated pain, reduced OARSI scores, improved cartilage matrix staining (Safranin O, Masson's trichrome), attenuated synovial hyperplasia and posterior capsule adhesions, and decreased plasma IL\u20111\u03b2 and IL\u201118 levels. Western blot of rat cartilage confirmed that SIN suppressed GSDMD and NLRP3 expression. These results indicate that SIN ameliorates OA progression by inhibiting SERPINA3\u2011mediated NF\u2011\u03baB\/NLRP3\u2011driven chondrocyte pyroptosis. SIN may be a potential therapeutic candidate for OA.<\/jats:p>","DOI":"10.4081\/ejh.2026.4587","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T12:02:25Z","timestamp":1791374545000},"source":"Crossref","is-referenced-by-count":0,"title":["Sinensetin ameliorates osteoarthritis progression by modulating the NF-\u03baB\/NLRP3 signaling pathway and suppressing chondrocyte pyroptosis"],"prefix":"10.4081","volume":"70","author":[{"given":"Zhendong","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruizhou","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peilai","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2549","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"53937","doi-asserted-by":"crossref","unstructured":"1. Abramoff BA, Caldera FE. Osteoarthritis: pathology, diagnosis, and treatment options. Med Clin North Am 2020;104:293-311.","DOI":"10.1016\/j.mcna.2019.10.007"},{"key":"53938","doi-asserted-by":"crossref","unstructured":"2. Brandt KD, Dieppe P, Radin EL. Etiopathogenesis of osteoarthritis. Rheum Dis Clin North Am 2008;34:531-59.","DOI":"10.1016\/j.rdc.2008.05.011"},{"key":"53939","doi-asserted-by":"crossref","unstructured":"3. Lories RJ, Luyten FP. The bone\u2013cartilage unit in osteoarthritis. Nat Rev Rheumatol 2011;7:43-9.","DOI":"10.1038\/nrrheum.2010.197"},{"key":"53940","doi-asserted-by":"crossref","unstructured":"4. Dreier R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res Ther 2010;12:216.","DOI":"10.1186\/ar3117"},{"key":"53941","doi-asserted-by":"crossref","unstructured":"5. Lee AS, Ellman MB, Yan D, Kroin JS, Cole BJ, van Wijnen AJ, et al. A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 2013;527:440-7.","DOI":"10.1016\/j.gene.2013.05.069"},{"key":"53942","doi-asserted-by":"crossref","unstructured":"6. Yu H, Zhu Y. Expression of ADAMTS-7 and ADAMTS-12 in the nucleus pulposus during degeneration of rat caudal intervetebral disc. J Vet Med Sci 2012;74:9-15.","DOI":"10.1292\/jvms.10-0556"},{"key":"53943","doi-asserted-by":"crossref","unstructured":"7. Chiu YS, Wu JL, Yeh CT, Yadav VK, Huang HS, Wang LS. \u03b3-Mangostin isolated from Garcinia mangostana L. suppresses inflammation and alleviates symptoms of osteoarthritis via modulating miR-124-3p\/IL-6\/NF-\u03baB signaling. Aging (Albany NY) 2020;12:6630-43.","DOI":"10.18632\/aging.103003"},{"key":"53944","doi-asserted-by":"crossref","unstructured":"8. Zhu M, Xu Q, Yang X, Zhan H, Zhang B, Liu X, et al. Vindoline attenuates osteoarthritis progression through suppressing the NF-\u03baB and ERK Pathways in both chondrocytes and subchondral osteoclasts. Front Pharmacol 2021;12:764598.","DOI":"10.3389\/fphar.2021.764598"},{"key":"53945","doi-asserted-by":"crossref","unstructured":"9. Zhao P, Lin L, Wu M, Wang L, Geng Q, Li L, et al. Targets preliminary screening for the fresh natural drug molecule based on Cosine-correlation and similarity-comparison of local network. J Transl Med 2022;20:67.","DOI":"10.1186\/s12967-022-03279-w"},{"key":"53946","doi-asserted-by":"crossref","unstructured":"10. Naeem A, Yu C, Liu Y, Feng Y, Fan J, Guan Y. Study of Gelatin-grafted-2-acrylamido-2-methylpropane sulfonic acid hydrogels as a controlled release vehicle for amorphous solid dispersion of Tripterygium Wilfordii bioactive constituents. Arab J Chem 2023;16:105139.","DOI":"10.1016\/j.arabjc.2023.105139"},{"key":"53947","doi-asserted-by":"crossref","unstructured":"11. Liu Z, Liu R, Wang R, Dai J, Chen H, Wang J, et al. Sinensetin attenuates IL-1\u03b2-induced cartilage damage and ameliorates osteoarthritis by regulating SERPINA3. Food Funct 2022;13:9973-87.","DOI":"10.1039\/D2FO01304E"},{"key":"53948","doi-asserted-by":"crossref","unstructured":"12. Zhang Y, Tao M, Chen C, Zhao X, Feng Q, Chen G, et al. BAFF blockade attenuates DSS-induced chronic colitis via inhibiting NLRP3 inflammasome and NF-\u03baB activation. Front Immunol 2022;13:783254.","DOI":"10.3389\/fimmu.2022.783254"},{"key":"53949","doi-asserted-by":"crossref","unstructured":"13. Ding R, Li H, Liu Y, Ou W, Zhang X, Chai H, et al. Activating cGAS-STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis. J Neuroinflammation 2022;19:137.","DOI":"10.1186\/s12974-022-02511-0"},{"key":"53950","doi-asserted-by":"crossref","unstructured":"14. Wan P, Su W, Zhang Y, Li Z, Deng C, Li J, et al. 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Castrogiovanni P, Di Rosa M, Ravalli S, Castorina A, Guglielmino C, Imbesi R, et al. Moderate physical activity as a prevention method for knee osteoarthritis and the role of synoviocytes as biological key. Int J Mol Sci 2019;20:511.","DOI":"10.3390\/ijms20030511"},{"key":"53957","doi-asserted-by":"crossref","unstructured":"21. Zhang Q, Bai X, Wang R, Zhao H, Wang L, Liu J, et al. 4-octyl Itaconate inhibits lipopolysaccharide (LPS)-induced osteoarthritis via activating Nrf2 signalling pathway. J Cell Mol Med 2022;26:1515-29.","DOI":"10.1111\/jcmm.17185"},{"key":"53958","doi-asserted-by":"crossref","unstructured":"22. Li S, Schwartz A V, LaValley M P, Wang N, Desai N, Sun X, et al. Association of visceral adiposity with pain but not structural osteoarthritis. Arthritis Rheumatol 2020;72:1103-10.","DOI":"10.1002\/art.41222"},{"key":"53959","doi-asserted-by":"crossref","unstructured":"23. Nguyen JP, Dixneuf V, Esnaut J, Moreno AS, Malineau C, Nizard J, et al. The value of high-frequency repetitive transcranial magnetic stimulation of the motor cortex to treat central pain sensitization associated with knee osteoarthritis. Front Neurosci 2019;13:388.","DOI":"10.3389\/fnins.2019.00388"},{"key":"53960","doi-asserted-by":"crossref","unstructured":"24. Wang Y, Ge W, Ma Z, Ji G, Wang M, Zhou G, et al. Use of mesoporous polydopamine nanoparticles as a stable drug-release system alleviates inflammation in knee osteoarthritis. APL Bioeng 2022;6:026101.","DOI":"10.1063\/5.0088447"},{"key":"53961","doi-asserted-by":"crossref","unstructured":"25. Al-Modawi RN, Brinchmann JE, Karlsen TA. Multi-pathway protective effects of MicroRNAs on human chondrocytes in an in vitro model of osteoarthritis. Mol Ther Nucleic Acids 2019;17:776-90.","DOI":"10.1016\/j.omtn.2019.07.011"},{"key":"53962","doi-asserted-by":"crossref","unstructured":"26. Cheleschi S, Gallo I, Barbarino M, Giannotti S, Mondanelli N, Giordano A, et al. MicroRNA mediate visfatin and resistin induction of oxidative stress in human osteoarthritic synovial fibroblasts via NF-\u03baB pathway. Int J Mol Sci 2019;20:5200.","DOI":"10.3390\/ijms20205200"},{"key":"53963","doi-asserted-by":"crossref","unstructured":"27. Linder A, Bauernfried S, Cheng Y, Albanese M, Jung C, Keppler OT, et al. CARD8 inflammasome activation triggers pyroptosis in human T cells. EMBO J 2020;39:e105071.","DOI":"10.15252\/embj.2020105071"},{"key":"53964","doi-asserted-by":"crossref","unstructured":"28. Luo J, Zhang M, Wang Z, Yan L, Liu Y. Anti\u2011\u03b2(2)GPI\/\u03b2(2)GPI induces neutrophil pyroptosis and thereby enhances ICAM\u20111 and IL\u20118 expression in endothelial cells. Int J Mol Med 2022;49:64.","DOI":"10.3892\/ijmm.2022.5120"},{"key":"53965","doi-asserted-by":"crossref","unstructured":"29. Wang M, Xia H, Yan Q, Liu W, Liu M, Wang X. 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ZFP36 promotes VDR mRNA degradation to facilitate cell death in oral and colonic epithelial cells. Cell Commun Signal 2021;19:85.","DOI":"10.1186\/s12964-021-00765-4"},{"key":"53969","doi-asserted-by":"crossref","unstructured":"33. Yu J W, Fernandes-Alnemri T, Datta P, Wu J, Juliana C, Solorzano L, et al. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol Cell 2007;28:214-27.","DOI":"10.1016\/j.molcel.2007.08.029"},{"key":"53970","doi-asserted-by":"crossref","unstructured":"34. Zeng J, Xie X, Feng X L, Xu L, Han J B, Yu D, et al. Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice. EBioMedicine 2022;75:103803.","DOI":"10.1016\/j.ebiom.2021.103803"},{"key":"53971","doi-asserted-by":"crossref","unstructured":"35. Qiao L, Zhang X, Pi S, Chang J, Dou X, Yan S, et al. Dietary supplementation with biogenic selenium nanoparticles alleviate oxidative stress-induced intestinal barrier dysfunction. NPJ Sci Food 2022;6:30.","DOI":"10.1038\/s41538-022-00145-3"},{"key":"53972","doi-asserted-by":"crossref","unstructured":"36. Wang F, Liu J, Chen X, Zheng X, Qu N, Zhang B, et al. IL-1\u03b2 receptor antagonist (IL-1Ra) combined with autophagy inducer (TAT-Beclin1) is an effective alternative for attenuating extracellular matrix degradation in rat and human osteoarthritis chondrocytes. Arthritis Res Ther 2019;21:171.","DOI":"10.1186\/s13075-019-1952-5"},{"key":"53973","doi-asserted-by":"crossref","unstructured":"37. Cheng L, Dong R, Song C, Li X, Zhang L, Shi M, et al. Mediation effects of IL-1\u03b2 and IL-18 on the association between vitamin D levels and mild cognitive impairment among Chinese older adults: a case-control study in Taiyuan, China. Front Aging Neurosci 2022;14:836311.","DOI":"10.3389\/fnagi.2022.836311"},{"key":"53974","doi-asserted-by":"crossref","unstructured":"38. Bao J, Chen Z, Xu L, Wu L, Xiong Y. Rapamycin protects chondrocytes against IL-18-induced apoptosis and ameliorates rat osteoarthritis. Aging (Albany NY) 2020;12:5152-67.","DOI":"10.18632\/aging.102937"},{"key":"53975","doi-asserted-by":"crossref","unstructured":"39. Attur M, Krasnokutsky S, Statnikov A, Samuels J, Li Z, Friese O, et al. Low-grade inflammation in symptomatic knee osteoarthritis: prognostic value of inflammatory plasma lipids and peripheral blood leukocyte biomarkers. Arthritis Rheumatol 2015;67:2905-15.","DOI":"10.1002\/art.39279"},{"key":"53976","doi-asserted-by":"crossref","unstructured":"40. Wu C, Li F, Zhang X, Xu W, Wang Y, Yao Y, et al. (-)-Epicatechin Ameliorates monosodium urate-induced acute gouty arthritis through inhibiting NLRP3 inflammasome and the NF-\u03baB signaling pathway. Front Pharmacol 2022;13:799552.","DOI":"10.3389\/fphar.2022.799552"},{"key":"53977","doi-asserted-by":"crossref","unstructured":"41. [41] Ramesova A, Vesela B, Svandova E, Lesot H, Matalova E. Caspase-1 inhibition impacts the formation of chondrogenic nodules, and the expression of markers related to osteogenic differentiation and lipid metabolism. Int J Mol Sci 2021;22:9576.","DOI":"10.3390\/ijms22179576"},{"key":"53978","doi-asserted-by":"crossref","unstructured":"42. Yan Z, Qi W, Zhan J, Lin Z, Lin J, Xue X, et al. Activating Nrf2 signalling alleviates osteoarthritis development by inhibiting inflammasome activation. J Cell Mol Med 2020;24:13046-57.","DOI":"10.1111\/jcmm.15905"},{"key":"53979","doi-asserted-by":"crossref","unstructured":"43. Lin Z, Wu D, Huang L, Jiang C, Pan T, Kang X, et al. Nobiletin inhibits IL-1\u03b2-induced inflammation in chondrocytes via suppression of NF-\u03baB signaling and attenuates osteoarthritis in mice. Front Pharmacol 2019;10:570.","DOI":"10.3389\/fphar.2019.00570"},{"key":"53980","doi-asserted-by":"crossref","unstructured":"44. Wang Y, Li Z, Wang B, Li K, Zheng J. Naringenin attenuates inflammation and apoptosis of osteoarthritic chondrocytes via the TLR4\/TRAF6\/NF-\u03baB pathway. PeerJ 2023;11:e16307.","DOI":"10.7717\/peerj.16307"},{"key":"53981","doi-asserted-by":"crossref","unstructured":"45. Zu Y, Mu Y, Li Q, Zhang S T, Yan H J. Icariin alleviates osteoarthritis by inhibiting NLRP3-mediated pyroptosis. J Orthop Surg Res 2019;14:307.","DOI":"10.1186\/s13018-019-1307-6"},{"key":"53982","doi-asserted-by":"crossref","unstructured":"46. Wang Q, Ying L, Wei B, Ji Y, Xu Y. Effects of quercetin on apoptosis and extracellular matrix degradation of chondrocytes induced by oxidative stress-mediated pyroptosis. J Biochem Mol Toxicol 2022;36:e22951.","DOI":"10.1002\/jbt.22951"},{"key":"53983","doi-asserted-by":"crossref","unstructured":"47. Bai H, Yuan R, Zhang Z, Liu L, Wang X, Song X, et al. Intra-articular injection of baicalein inhibits cartilage catabolism and NLRP3 inflammasome signaling in a posttraumatic OA model. Oxid Med Cell Longev 2021;2021:6116890.","DOI":"10.1155\/2021\/6116890"},{"key":"53984","doi-asserted-by":"crossref","unstructured":"48. Ding L, Liao T, Yang N, Wei Y, Xing R, Wu P, et al. Chrysin ameliorates synovitis and fibrosis of osteoarthritic fibroblast-like synoviocytes in rats through PERK\/TXNIP\/NLRP3 signaling. 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