{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T05:21:10Z","timestamp":1787721670530,"version":"build-2784847793"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cartilage injury is a hallmark of osteoarthritis (OA). erb-B2 receptor tyrosine kinase 2 (ERBB2) has been reported to be involved in mediating the therapeutic effects of polyphenols in orthopedic diseases. This study aimed to investigate the protective effects and underlying mechanisms of action of ERBB2 in OA chondrocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bioinformatics analysis and molecular docking were used to predict the binding relationship between ERBB2 and the polyphenolic compound, secoisolariciresinol diglucoside (SDG). ATDC5 cells were induced with insulin-transferrin-selenium (ITS), followed by lipopolysaccharide (LPS) exposure to mimic OA inflammation, and treated with SDG. Cell viability, collagen II expression, apoptosis, interleukin 6 (IL-6)\/Tumor Necrosis Factor-\u03b1 (TNF-\u03b1) secretion, and malondialdehyde (MDA)\/superoxide dismutase (SOD) levels were evaluated using cell counting kit-8 (CCK-8), immunofluorescence, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and commercial kits. Matrix metalloproteinase 13 (MMP13) and ERBB2 mRNA levels were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Extracellular matrix integrity was assessed by toluidine blue staining. The predicted SDG-ERBB2 interaction was validated using a cellular thermal shift assay (CETSA). Western blotting was performed to assess the expression of ERBB2 and JAK2\/STAT3. Rescue experiments with ERBB2 overexpression or colivelin (a JAK\/STAT activator) treatment confirmed the involvement of this pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SDG dose-dependently reversed the LPS-induced reduction in cell viability and collagen II expression, while suppressing apoptosis, IL-6\/TNF-\u03b1 secretion, and MDA levels, and increasing SOD activity. SDG significantly reduced MMP13 mRNA levels and enhanced extracellular matrix proteoglycan deposition, indicating the preservation of matrix integrity. ERBB2 has been identified as a candidate target for SDG. SDG inhibits ERBB2 protein expression and reduces JAK2 and STAT3 phosphorylation ERBB2 overexpression and colivelin treatment abrogated the protective effects of SDG on cell viability, collagen II expression, apoptosis, inflammation, and oxidative stress, as well as its suppression of MMP13 and preservation of matrix integrity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>SDG protects chondrocytes against LPS-induced inflammatory injury by targeting ERBB2 and suppressing the downstream JAK2\/STAT3 signaling pathway. These findings provide mechanistic evidence supporting the chondroprotective potential of SDG under inflammatory conditions and suggest that ERBB2\/JAK2\/STAT3 signaling may represent a potential therapeutic target in OA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1891212","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T04:53:19Z","timestamp":1787719999000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Secoisolariciresinol diglucoside alleviates inflammatory injury in osteoarthritis chondrocytes through ERBB2-associated JAK2\/STAT3 signaling: network pharmacology and experimental validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Haibei","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, Anhui Key Laboratory of Tissue Transplantation","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaoshan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, 968 Hospital of Joint Service Support Force of Chinese People\u2019s Liberation Army","place":["Jinzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangxu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, Anhui Key Laboratory of Tissue Transplantation","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyu","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, Anhui Key Laboratory of Tissue Transplantation","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, Anhui Key Laboratory of Tissue Transplantation","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, Anhui Key Laboratory of Tissue Transplantation","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xubin","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, Anhui Key Laboratory of Tissue Transplantation","place":["Bengbu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.54254\/2753-8818\/21\/20230871","article-title":"Osteoarthritis","volume":"11","author":"Tang","year":"2025","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2024.07.014","article-title":"Osteoarthritis year in review 2024: Epidemiology and therapy","volume":"32","author":"Courties","year":"2024","journal-title":"Osteoarthritis Cartilage"},{"key":"B3","doi-asserted-by":"publisher","first-page":"33","DOI":"10.2174\/012772574x270405231102054920","article-title":"A systemic review on nutraceutical supplements used in the management of osteoarthritis","volume":"15","author":"Nooreen","year":"2024","journal-title":"Recent Adv Food Nutr Agric"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.8455","article-title":"Unraveling the molecular mechanisms of osteoarthritis: The potential of polyphenols as therapeutic agents","volume":"39","author":"Rahaman","year":"2025","journal-title":"Phytother Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23116031","article-title":"Lignans as pharmacological agents in disorders related to oxidative stress and inflammation: Chemical synthesis approaches and biological activities","volume":"23","author":"Osmakov","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B6","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s11914-024-00883-1","article-title":"Lignans from Sambucus williamsii protect bone via microbiome","volume":"22","author":"Xiao","year":"2024","journal-title":"Curr Osteoporos Rep"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/3621261","article-title":"Secoisolariciresinol diglucoside exerts anti-inflammatory and antiapoptotic effects through inhibiting the Akt\/I\u03baB\/NF-\u03baB pathway on human umbilical vein endothelial cells","volume":"2020","author":"Zhang","year":"2020","journal-title":"Mediators Inflammation"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114964","article-title":"Secoisolariciresinol diglucoside ameliorates osteoarthritis via nuclear factor-erythroid 2-related factor-2\/ nuclear factor kappa B pathway: In vitro and in vivo experiments","volume":"164","author":"Zhang","year":"2023","journal-title":"BioMed Pharmacother"},{"key":"B9","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/s41584-025-01236-7","article-title":"Restoring articular cartilage: Insights from structure, composition and development","volume":"21","author":"Pueyo Moliner","year":"2025","journal-title":"Nat Rev Rheumatol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.apsb.2022.09.020","article-title":"Roles of focal adhesion proteins in skeleton and diseases","volume":"13","author":"Chen","year":"2023","journal-title":"Acta Pharm Sin B"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2025.104436","article-title":"ErbB\/HER family in cancer immunology: Therapeutic advances and mechanisms","volume":"30","author":"Yin","year":"2025","journal-title":"Drug Discov Today"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2024.04.009","article-title":"Emerging paradigms and recent progress in targeting ErbB in cancers","volume":"45","author":"Stoup","year":"2024","journal-title":"Trends Pharmacol Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2026.150525","article-title":"Stage-specific miRNA signatures in osteoarthritis identify miR-4505 and miR-331-3p as key modulators of disease pathogenesis via ERBB2 suppression","volume":"345","author":"Rana","year":"2026","journal-title":"Int J Biol Macromol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1069057","article-title":"The potential roles of JAK\/STAT signaling in the progression of osteoarthritis","volume":"13","author":"Zhou","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/cnr2.1974","article-title":"miRNA-449c-5p regulates the JAK-STAT pathway in inhibiting cell proliferation and invasion in human breast cancer cells by targeting ERBB2","volume":"7","author":"Li","year":"2024","journal-title":"Cancer Rep (Hoboken NJ)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00856-y","article-title":"Targeting IL-6 trans-signalling: Past, present and future prospects","volume":"23","author":"Rose-John","year":"2023","journal-title":"Nat Rev Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.866014","article-title":"IL-6\/JAK\/STAT3 signaling in breast cancer metastasis: Biology and treatment","volume":"12","author":"Manore","year":"2022","journal-title":"Front Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.sabcs15-pd3-03","article-title":"Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-\/HER2+ breast cancers","volume":"29","author":"Rodriguez-Barrueco","year":"2015","journal-title":"Genes Dev"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abn7082","article-title":"Interleukin-6 signaling mediates cartilage degradation and pain in posttraumatic osteoarthritis in a sex-specific manner","volume":"15","author":"Liao","year":"2022","journal-title":"Sci Signaling"},{"key":"B20","doi-asserted-by":"publisher","first-page":"29602","DOI":"10.1038\/s41598-025-14896-y","article-title":"Dehydrotanshinone II A alleviates osteoarthritis via activating PPAR\u03b3 to inhibit ferroptosis in chondrocytes","volume":"15","author":"Guan","year":"2025","journal-title":"Sci Rep"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1080\/15384047.2022.2051158","article-title":"GANT61 suppresses cell survival, invasion and epithelial-mesenchymal transition through inactivating AKT\/mTOR and JAK\/STAT3 pathways in anaplastic thyroid carcinoma","volume":"23","author":"Gao","year":"2022","journal-title":"Cancer Biol Ther"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2893","DOI":"10.3390\/nu12092893","article-title":"Dietary polyphenols and human health","volume":"12","author":"Tresserra-Rimbau","year":"2020","journal-title":"Nutrients"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.156717","article-title":"The antidiabetic properties of lignans: A comprehensive review","volume":"141","author":"Isah","year":"2025","journal-title":"Phytomedicine Int J Phytotherapy Phytopharmacology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232415482","article-title":"Antioxidant, anti-inflammatory, anti-menopausal, and anti-cancer effects of lignans and their metabolites","volume":"23","author":"Jang","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B25","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1021\/np4004905","article-title":"Permeability and conjugative metabolism of flaxseed lignans by Caco-2 human intestinal cells","volume":"77","author":"Mukker","year":"2014","journal-title":"J Nat Prod"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3945\/jn.112.162453","article-title":"Among plant lignans, pinoresinol has the strongest antiinflammatory properties in human intestinal Caco-2 cells","volume":"142","author":"During","year":"2012","journal-title":"J Nutr"},{"key":"B27","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1186\/s13018-023-04284-5","article-title":"Secoisolariciresinol diglucoside regulates estrogen receptor expression to ameliorate OVX-induced osteoporosis","volume":"18","author":"Chen","year":"2023","journal-title":"J Orthop Surg Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1080\/07853890.2025.2548045","article-title":"Multi-omics analysis and validation of autophagy-related diagnostic biomarker in osteoarthritis","volume":"57","author":"Cai","year":"2025","journal-title":"Ann Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/3482751","article-title":"Identification of key genes and pathways associated with sex differences in osteoarthritis based on bioinformatics analysis","volume":"2019","author":"Wang","year":"2019","journal-title":"BioMed Res Int"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1080\/03009740510017715","article-title":"TGF-alpha and ErbB2 production in synovial joint tissue: Increased expression in arthritic joints","volume":"34","author":"Hallbeck","year":"2005","journal-title":"Scandinavian J Rheumatol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/s12964-023-01094-4","article-title":"Regulation and therapy, the role of JAK2\/STAT3 signaling pathway in OA: A systematic review","volume":"21","author":"Chen","year":"2023","journal-title":"Cell Commun Signal"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2024.06.002","article-title":"The involvement of signaling pathways in the pathogenesis of osteoarthritis: An update","volume":"47","author":"Fazio","year":"2024","journal-title":"J Orthopaedic Translation"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1134\/s0006297920100156","article-title":"The role of ERBB2\/HER2 tyrosine kinase receptor in the regulation of cell death","volume":"85","author":"Daks","year":"2020","journal-title":"Biochem Biokhimiia"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2022.109039","article-title":"Secoisolariciresinol diglucoside-derived metabolite, enterolactone, attenuates atopic dermatitis by suppressing Th2 immune response","volume":"111","author":"Yu","year":"2022","journal-title":"Int Immunopharmacol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m110773200","article-title":"JAK\/STAT but not ERK1\/ERK2 pathway mediates interleukin (IL)-6\/soluble IL-6R down-regulation of Type II collagen, aggrecan core, and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression","volume":"278","author":"Legendre","year":"2003","journal-title":"J Biol Chem"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/life15081238","article-title":"Breaking down osteoarthritis: Exploring inflammatory and mechanical signaling pathways","volume":"15","author":"Batarfi","year":"2025","journal-title":"Life (Basel Switzerland)"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1891212\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T04:53:37Z","timestamp":1787720017000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1891212\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":36,"alternative-id":["10.3389\/fimmu.2026.1891212"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1891212","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]},"article-number":"1891212"}}