{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T06:53:01Z","timestamp":1781679181109,"version":"3.54.5"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"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. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive synovial inflammation, cartilage and bone destruction. Although granzyme B (GZMB) can prevent osteocartilaginous destruction and promote bone formation, its effects and molecular mechanisms in RA remain unclear. We therefore explored the effects of GZMB on RA development at the cellular level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed the effects of GZMB on MH7A\u00a0cell proliferation using Cell Counting Kit-8 assays. Migration and invasion were detected using wound healing and Transwell\u00ae assays, respectively, and the cell cycle and apoptosis were assessed using flow cytometry. Additionally, 24 Sprague-Dawley (SD) rats were divided into sham, RA, and RA + GZMB inhibitor groups. Pathological changes, inflammatory factors, and related proteins were assessed in each group after treatment. Furthermore, we evaluated correlations between GZMB and the phosphoinositide 3-kinase (PI3K)\/protein kinase B (AKT) pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Granzyme B suppressed cell proliferation, migration and invasion\n                      <jats:italic>in vitro<\/jats:italic>\n                      , promoted apoptosis, and increased the proportion of cells in the S and G2 phases. Additionally, histological staining revealed that after GZMB inhibitor treatment, the articular cartilage surface of rats in the GZMB inhibitor group was smooth, and synovial tissue hyperplasia and inflammatory cell infiltration were reduced. Moreover, GZMB regulated expression of the PI3K\/AKT signaling pathway during RA treatment\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings suggest that GZMB knockdown suppresses cell proliferation, migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis, and alleviates the progression of RA rats. This therapeutic mechanism may involve regulation of the PI3K\/AKT pathway.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1679672","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:56:37Z","timestamp":1781675797000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Granzyme B knockdown suppresses cell proliferation, migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis"],"prefix":"10.3389","volume":"14","author":[{"given":"Wei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Affiliated Hospital of North Sichuan Medical College","place":["Nanchong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weike","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Affiliated Hospital of North Sichuan Medical College","place":["Nanchong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Affiliated Hospital of North Sichuan Medical College","place":["Nanchong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"696802","DOI":"10.3389\/fphar.2021.696802","article-title":"WTD attenuating rheumatoid arthritis via suppressing angiogenesis and modulating the PI3K\/AKT\/mTOR\/HIF-1\u03b1 pathway","volume":"12","author":"Ba","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1111\/j.0105-2896.2009.00859.x","article-title":"Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis","volume":"233","author":"Bartok","year":"2010","journal-title":"Immunol. Rev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/j.biopha.2018.04.023","article-title":"Expression of concern: GZMB gene silencing confers protection against synovial tissue hyperplasia and articular cartilage tissue injury in rheumatoid arthritis through the MAPK signaling pathway","volume":"103","author":"Bao","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"B4","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1038\/s41419-022-05065-4","article-title":"Semaphorin 5A suppresses ferroptosis through activation of PI3K-AKT-mTOR signaling in rheumatoid arthritis","volume":"13","author":"Cheng","year":"2022","journal-title":"Cell Death Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/j.immuni.2022.03.004","article-title":"Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones","volume":"55","author":"Collora","year":"2022","journal-title":"Immunity"},{"key":"B6","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.rdc.2022.02.010","article-title":"Rheumatoid arthritis: early diagnosis and treatment","volume":"48","author":"Cush","year":"2022","journal-title":"Rheum. Dis. Clin. North Am."},{"key":"B7","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.jcyt.2021.10.003","article-title":"Rheumatoid arthritis: from synovium biology to cell-based therapy","volume":"24","author":"Debreova","year":"2022","journal-title":"Cytotherapy"},{"key":"B8","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.medcle.2023.07.008","article-title":"Rheumatoid arthritis","volume":"161","author":"D\u00edaz-Gonz\u00e1lez","year":"2023","journal-title":"Med. Clin. Barc."},{"key":"B9","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/s12943-023-01827-6","article-title":"PI3K\/AKT\/mTOR signaling transduction pathway and targeted therapies in cancer","volume":"22","author":"Glaviano","year":"2023","journal-title":"Mol. Cancer"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e32","DOI":"10.1056\/NEJMp2310178","article-title":"Schubach A: what is rheumatoid arthritis?","volume":"390","author":"Gravallese","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"686155","DOI":"10.3389\/fimmu.2021.686155","article-title":"Promising therapeutic targets for treatment of rheumatoid arthritis","volume":"12","author":"Huang","year":"2021","journal-title":"Front. Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"14509","DOI":"10.3390\/ijms241914509","article-title":"Etiology and pathogenesis of rheumatoid arthritis-interstitial lung disease","volume":"24","author":"Kim","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"10922","DOI":"10.3390\/ijms222010922","article-title":"Cytokine networks in the pathogenesis of rheumatoid arthritis","volume":"22","author":"Kondo","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"118625","DOI":"10.1016\/j.ijpharm.2019.118625","article-title":"Targeted and MMP-2\/9 responsive peptides for the treatment of rheumatoid arthritis","volume":"569","author":"Li","year":"2019","journal-title":"Int. J. Pharm."},{"key":"B15","doi-asserted-by":"publisher","first-page":"912933","DOI":"10.3389\/fimmu.2022.912933","article-title":"A novel drug combination of mangiferin and cinnamic acid alleviates rheumatoid arthritis by inhibiting TLR4\/NF\u03baB\/NLRP3 activation-induced pyroptosis","volume":"13","author":"Li","year":"2022","journal-title":"Front. Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.cell.2023.12.015","article-title":"Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death","volume":"187","author":"Li","year":"2024","journal-title":"Cell"},{"key":"B17","doi-asserted-by":"publisher","first-page":"880","DOI":"10.3390\/cells9040880","article-title":"Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis","volume":"9","author":"Lin","year":"2020","journal-title":"Cells"},{"key":"B18","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":"B19","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":"B20","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/S2215-0366(18)30255-4","article-title":"Rheumatoid arthritis and depression: an inflammatory perspective","volume":"6","author":"Nerurkar","year":"2019","journal-title":"Lancet Psychiatry"},{"key":"B21","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.joca.2005.07.014","article-title":"Osteoarthritis cartilage histopathology: grading and staging","volume":"14","author":"Pritzker","year":"2006","journal-title":"Osteoarthr. Cartil."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2857","DOI":"10.3390\/cells10112857","article-title":"Management of rheumatoid arthritis: an overview","volume":"10","author":"Radu","year":"2021","journal-title":"Cells"},{"key":"B23","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":"B24","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1007\/s00296-017-3732-3","article-title":"Genomics, transcriptomics and proteomics to elucidate the pathogenesis of rheumatoid arthritis","volume":"37","author":"Song","year":"2017","journal-title":"Rheumatol. Int."},{"key":"B25","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":"B26","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":"B27","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1038\/s41590-019-0378-1","article-title":"Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry","volume":"20","author":"Zhang","year":"2019","journal-title":"Nat. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.molimm.2023.07.013","article-title":"Exploring the molecular mechanisms of the involvement of GZMB-Caspase-3-GSDME pathway in the progression of rheumatoid arthritis","volume":"161","author":"Zhang","year":"2023","journal-title":"Mol. Immunol."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1679672\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:56:38Z","timestamp":1781675798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1679672\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":28,"alternative-id":["10.3389\/fcell.2026.1679672"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1679672","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]},"article-number":"1679672"}}