{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:33:34Z","timestamp":1793043214890,"version":"4.5.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Jiangsu Comission of Health","award":["LKM2022074"],"award-info":[{"award-number":["LKM2022074"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Purpose<\/jats:title>\n            <jats:p>Osteoarthritis (OA) is a debilitating joint disease with no effective cure. This study investigates the role of Insulin Receptor Substrate 2 (IRS2) in OA and its potential as a therapeutic target.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Transcriptomic analysis of OA-related datasets (GSE178557, GSE169077, GSE64394, GSE57218) was conducted to identify differentially expressed genes (DEGs), with KEGG pathway analysis highlighting the PI3K\/AKT pathway. In vivo, the destabilization of the medial meniscus (DMM) OA mouse model was used to assess IRS2 expression through histology, qPCR, and Western blot. IRS2 was overexpressed in primary mouse chondrocytes via adenoviral transfection, with proliferation, apoptosis, and autophagy assessed by EdU, Annexin V\/PI staining, and autophagy-related protein analysis. Adenovirus expressing Irs2 was injected intra-articularly into DMM mice, and cartilage integrity was assessed using histology and micro-CT.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>IRS2 expression was significantly reduced in OA cartilage, correlating with PI3K\/AKT pathway inhibition. IRS2 overexpression restored AKT activation, FOXO1 phosphorylation, and mitochondrial autophagy. Intra-articular IRS2 injection improved cartilage matrix integrity, reduced MMP13, and alleviated subchondral bone changes in DMM mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>IRS2 plays a key role in OA pathogenesis and targeting it may provide a promising therapeutic approach for OA.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s10020-025-01346-8","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T10:34:15Z","timestamp":1758882855000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["IRS2\/FOXO1 mitigates osteoarthritis by regulating chondrocyte autophagy and mitochondrial function"],"prefix":"10.1186","volume":"31","author":[{"given":"Chaoren","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changjiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaohui","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoyou","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"issue":"2","key":"1346_CR1","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.joca.2021.04.020","volume":"30","author":"KD Allen","year":"2022","unstructured":"Allen KD, Thoma LM, Golightly YM. Epidemiology of osteoarthritis. Osteoarthr Cartil. 2022;30(2):184\u201395.","journal-title":"Osteoarthr Cartil"},{"issue":"1","key":"1346_CR2","doi-asserted-by":"publisher","first-page":"46","DOI":"10.7326\/M14-1231","volume":"162","author":"RR Bannuru","year":"2015","unstructured":"Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of Pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015;162(1):46\u201354.","journal-title":"Ann Intern Med"},{"key":"1346_CR3","doi-asserted-by":"crossref","unstructured":"Scheuing, W. J., Reginato, A. M., Deeb, M., & Kasman, S. A. (2023). The burden of osteoarthritis: Is it a rising problem?. Best Practice & Research Clinical Rheumatology, 37(2), 101836.","DOI":"10.1016\/j.berh.2023.101836"},{"issue":"null","key":"1346_CR4","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.2147\/JPR.S154002","volume":"11","author":"JC Mora","year":"2018","unstructured":"Mora JC, Przkora R, Cruz-Almeida Y. Knee osteoarthritis: pathophysiology and current treatment modalities. J Pain Res. 2018;11(null):2189\u201396.","journal-title":"J Pain Res"},{"key":"1346_CR5","doi-asserted-by":"crossref","unstructured":"Cui A, Li H, Wang D, Zhong J, Chen Y, Lu H. Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies. EClinicalMedicine. 2020;29-30:100587.","DOI":"10.1016\/j.eclinm.2020.100587"},{"issue":"10","key":"1346_CR6","doi-asserted-by":"publisher","first-page":"2182","DOI":"10.1007\/s00125-020-05212-6","volume":"63","author":"C Krause","year":"2020","unstructured":"Krause C, Gei\u00dfler C, Tackenberg H, El Gammal AT, Wolter S, Spranger J, et al. Multi-layered epigenetic regulation of IRS2 expression in the liver of obese individuals with type 2 diabetes. Diabetologia. 2020;63(10):2182\u201393.","journal-title":"Diabetologia"},{"issue":"2","key":"1346_CR7","doi-asserted-by":"publisher","first-page":"L416","DOI":"10.1152\/ajplung.00068.2020","volume":"321","author":"M Nakahara","year":"2021","unstructured":"Nakahara M, Ito H, Skinner JT, Lin Q, Tamosiuniene R, Nicolls MR, et al. The inflammatory role of dysregulated IRS2 in pulmonary vascular remodeling under hypoxic conditions. Am J Physiol Lung Cell Mol Physiol. 2021;321(2):L416\u201328.","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"1346_CR8","doi-asserted-by":"crossref","unstructured":"Zhu S, Ward BM, Yu J, Matthew-Onabanjo AN, Janusis J, Hsieh CC, et al. IRS2 mutations linked to invasion in pleomorphic invasive lobular carcinoma. JCI Insight. 2018;3(8).","DOI":"10.1172\/jci.insight.97398"},{"issue":"4","key":"1346_CR9","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.cmet.2017.03.004","volume":"25","author":"T Kubota","year":"2017","unstructured":"Kubota T, Kubota N, Kadowaki T. Imbalanced insulin actions in obesity and type 2 diabetes: key mouse models of insulin signaling pathway. Cell Metab. 2017;25(4):797\u2013810.","journal-title":"Cell Metab"},{"issue":"8","key":"1346_CR10","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1016\/j.ajhg.2023.06.010","volume":"110","author":"AL Arruda","year":"2023","unstructured":"Arruda AL, Hartley A, Katsoula G, Smith GD, Morris AP, Zeggini E. Genetic underpinning of the comorbidity between type 2 diabetes and osteoarthritis. Am J Hum Genet. 2023;110(8):1304\u201318.","journal-title":"Am J Hum Genet"},{"issue":"3","key":"1346_CR11","doi-asserted-by":"publisher","first-page":"e233646","DOI":"10.1001\/jamanetworkopen.2023.3646","volume":"6","author":"MC Baker","year":"2023","unstructured":"Baker MC, Sheth K, Liu Y, Lu D, Lu R, Robinson WH. Development of osteoarthritis in adults with type 2 diabetes treated with Metformin vs a sulfonylurea. JAMA Netw Open. 2023;6(3):e233646.","journal-title":"JAMA Netw Open"},{"issue":"1","key":"1346_CR12","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s41467-020-20500-w","volume":"12","author":"A Kumar","year":"2021","unstructured":"Kumar A, Sundaram K, Mu J, Dryden GW, Sriwastva MK, Lei C, et al. High-fat diet-induced upregulation of Exosomal phosphatidylcholine contributes to insulin resistance. Nat Commun. 2021;12(1):213.","journal-title":"Nat Commun"},{"issue":"5","key":"1346_CR13","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1083\/jcb.200510065","volume":"172","author":"A Yamamoto","year":"2006","unstructured":"Yamamoto A, Cremona ML, Rothman JE. Autophagy-mediated clearance of Huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol. 2006;172(5):719\u201331.","journal-title":"J Cell Biol"},{"key":"1346_CR14","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.freeradbiomed.2018.08.038","volume":"132","author":"JA Bolduc","year":"2019","unstructured":"Bolduc JA, Collins JA, Loeser RF. Reactive oxygen species, aging and articular cartilage homeostasis. Free Radic Biol Med. 2019;132:73\u201382.","journal-title":"Free Radic Biol Med"},{"issue":"9","key":"1346_CR15","doi-asserted-by":"publisher","first-page":"2082","DOI":"10.1080\/15548627.2020.1822097","volume":"17","author":"K Sun","year":"2021","unstructured":"Sun K, Jing X, Guo J, Yao X, Guo F. Mitophagy in degenerative joint diseases. Autophagy. 2021;17(9):2082\u201392.","journal-title":"Autophagy"},{"key":"1346_CR16","doi-asserted-by":"publisher","first-page":"111688","DOI":"10.1016\/j.mad.2022.111688","volume":"205","author":"N Jiang","year":"2022","unstructured":"Jiang N, Xing B, Peng R, Shang J, Wu B, Xiao P, et al. Inhibition of Cpt1a alleviates oxidative stress-induced chondrocyte senescence via regulating mitochondrial dysfunction and activating mitophagy. Mech Ageing Dev. 2022;205:111688.","journal-title":"Mech Ageing Dev"},{"issue":"7621","key":"1346_CR17","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1136\/bmj.39339.610000.BE","volume":"335","author":"MD Goodyear","year":"2007","unstructured":"Goodyear MD, Krleza-Jeric K, Lemmens T. The declaration of Helsinki. BMJ. 2007;335(7621):624\u20135.","journal-title":"BMJ"},{"issue":"1","key":"1346_CR18","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1186\/1471-2105-13-335","volume":"13","author":"J Taminau","year":"2012","unstructured":"Taminau J, Meganck S, Lazar C, Steenhoff D, Coletta A, Molter C, et al. Unlocking the potential of publicly available microarray data using InSilicoDb and insilicomerging r\/bioconductor packages. BMC Bioinformatics. 2012;13(1):335.","journal-title":"BMC Bioinformatics"},{"issue":"1","key":"1346_CR19","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","volume":"8","author":"WE Johnson","year":"2007","unstructured":"Johnson WE, Li C, Rabinovic A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2007;8(1):118\u201327.","journal-title":"Biostatistics"},{"issue":"7","key":"1346_CR20","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.","journal-title":"Nucleic Acids Res"},{"key":"1346_CR21","doi-asserted-by":"crossref","unstructured":"Chen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA. Profiling tumor infiltrating immune cells with CIBERSORT. Methods Mol Biol. 2018:243\u201359.","DOI":"10.1007\/978-1-4939-7493-1_12"},{"issue":"1","key":"1346_CR22","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.mce.2006.02.002","volume":"249","author":"C Phornphutkul","year":"2006","unstructured":"Phornphutkul C, Wu K-Y, Gruppuso PA. The role of insulin in chondrogenesis. Mol Cell Endocrinol. 2006;249(1):107\u201315.","journal-title":"Mol Cell Endocrinol"},{"issue":"Pt 2","key":"1346_CR23","first-page":"129004","volume":"258","author":"J Xu","year":"2023","unstructured":"Xu J, Yu Y, Chen K, Wang Y, Zhu Y, Zou X, et al. Astragalus polysaccharides ameliorate osteoarthritis via inhibiting apoptosis by regulating ROS-mediated ASK1\/p38 MAPK signaling pathway targeting on TXN. Int J Biol Macromol. 2023;258(Pt 2):129004.","journal-title":"Int J Biol Macromol"},{"issue":"9","key":"1346_CR24","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1016\/j.joca.2007.03.006","volume":"15","author":"S Glasson","year":"2007","unstructured":"Glasson S, Blanchet T, Morris E. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129\/svev mouse. Osteoarthr Cartil. 2007a;15(9):1061\u20139.","journal-title":"Osteoarthr Cartil"},{"issue":"12","key":"1346_CR25","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1369\/0022155417733708","volume":"65","author":"FM Savi","year":"2017","unstructured":"Savi FM, Brierly GI, Baldwin J, Theodoropoulos C, Woodruff MA. Comparison of different decalcification methods using rat mandibles as a model. J Histochem Cytochem. 2017;65(12):705\u201322.","journal-title":"J Histochem Cytochem"},{"issue":"48","key":"1346_CR26","doi-asserted-by":"publisher","first-page":"30488","DOI":"10.1073\/pnas.2017056117","volume":"117","author":"C Wang","year":"2020","unstructured":"Wang C, Shen J, Ying J, Xiao D, O\u2019Keefe RJ. FoxO1 is a crucial mediator of TGF-\u03b2\/TAK1 signaling and protects against osteoarthritis by maintaining articular cartilage homeostasis. Proc Natl Acad Sci. 2020;117(48):30488\u201397.","journal-title":"Proc Natl Acad Sci"},{"issue":"1","key":"1346_CR27","doi-asserted-by":"publisher","first-page":"11023","DOI":"10.1038\/ncomms11023","volume":"7","author":"S Wang","year":"2016","unstructured":"Wang S, Xia P, Huang G, Zhu P, Liu J, Ye B, et al. FoxO1-mediated autophagy is required for NK cell development and innate immunity. Nat Commun. 2016;7(1):11023.","journal-title":"Nat Commun"},{"issue":"12","key":"1346_CR28","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.4161\/auto.21830","volume":"8","author":"J Zhou","year":"2012","unstructured":"Zhou J, Liao W, Yang J, Ma K, Li X, Wang Y, et al. FOXO3 induces FOXO1-dependent autophagy by activating the AKT1 signaling pathway. Autophagy. 2012;8(12):1712\u201323.","journal-title":"Autophagy"},{"issue":"5","key":"1346_CR29","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1007\/s00125-021-05415-5","volume":"64","author":"TM Batista","year":"2021","unstructured":"Batista TM, Haider N, Kahn CR. Defining the underlying defect in insulin action in type 2 diabetes. Diabetologia. 2021;64(5):994\u20131006.","journal-title":"Diabetologia"},{"issue":"1","key":"1346_CR30","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1172\/JCI25735","volume":"116","author":"X Dong","year":"2006","unstructured":"Dong X, Park S, Lin X, Copps K, Yi X, White MF. Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. J Clin Investig. 2006;116(1):101\u201314.","journal-title":"J Clin Investig"},{"issue":"4","key":"1346_CR31","doi-asserted-by":"publisher","first-page":"981","DOI":"10.2337\/db15-0529","volume":"65","author":"RE Stamateris","year":"2016","unstructured":"Stamateris RE, Sharma RB, Kong Y, Ebrahimpour P, Panday D, Ranganath P, et al. Glucose induces mouse \u03b2-Cell proliferation via IRS2, MTOR, and Cyclin D2 but not the insulin receptor. Diabetes. 2016;65(4):981\u201395.","journal-title":"Diabetes"},{"issue":"9","key":"1346_CR32","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1016\/j.joca.2016.04.007","volume":"24","author":"EDG Garessus","year":"2016","unstructured":"Garessus EDG, de Mutsert R, Visser AW, Rosendaal FR, Kloppenburg M. No association between impaired glucose metabolism and osteoarthritis. Osteoarthr Cartil. 2016;24(9):1541\u20137.","journal-title":"Osteoarthr Cartil"},{"issue":"1","key":"1346_CR33","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.semarthrit.2019.01.005","volume":"49","author":"N Veronese","year":"2019","unstructured":"Veronese N, Cooper C, Reginster J-Y, Hochberg M, Branco J, Bruy\u00e8re O, et al. Type 2 diabetes mellitus and osteoarthritis. Semin Arthritis Rheum. 2019;49(1):9\u201319.","journal-title":"Semin Arthritis Rheum"},{"issue":"9","key":"1346_CR34","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1016\/j.joca.2015.04.026","volume":"23","author":"MC Laiguillon","year":"2015","unstructured":"Laiguillon MC, Courties A, Houard X, Auclair M, Sautet A, Capeau J, et al. Characterization of diabetic Osteoarthritic cartilage and role of high glucose environment on chondrocyte activation: toward pathophysiological delineation of diabetes mellitus-related osteoarthritis. Osteoarthr Cartil. 2015;23(9):1513\u201322.","journal-title":"Osteoarthr Cartil"},{"issue":"5836","key":"1346_CR35","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1126\/science.1142179","volume":"317","author":"A Taguchi","year":"2007","unstructured":"Taguchi A, Wartschow LM, White MF. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science. 2007;317(5836):369\u201372.","journal-title":"Science"},{"key":"1346_CR36","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.lfs.2017.11.030","volume":"193","author":"YQ Xing","year":"2018","unstructured":"Xing YQ, Li A, Yang Y, Li XX, Zhang LN, Guo HC. The regulation of FOXO1 and its role in disease progression. Life Sci. 2018;193:124\u201331.","journal-title":"Life Sci"},{"issue":"6","key":"1346_CR37","doi-asserted-by":"publisher","first-page":"3135","DOI":"10.1073\/pnas.1918673117","volume":"117","author":"KI Lee","year":"2020","unstructured":"Lee KI, Choi S, Matsuzaki T, Alvarez-Garcia O, Olmer M, Grogan SP, et al. FOXO1 and FOXO3 transcription factors have unique functions in meniscus development and homeostasis during aging and osteoarthritis. Proc Natl Acad Sci. 2020;117(6):3135\u201343.","journal-title":"Proc Natl Acad Sci"},{"issue":"11","key":"1346_CR38","doi-asserted-by":"publisher","first-page":"3075","DOI":"10.1111\/jcmm.17319","volume":"26","author":"J Yue","year":"2022","unstructured":"Yue J, Aobulikasimu A, Sun W, Liu S, Xie W, Sun W. Targeted regulation of FoxO1 in chondrocytes prevents age-related osteoarthritis via autophagy mechanism. J Cell Mol Med. 2022;26(11):3075\u201382.","journal-title":"J Cell Mol Med"},{"issue":"7","key":"1346_CR39","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/ncb2069","volume":"12","author":"Y Zhao","year":"2010","unstructured":"Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S, et al. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol. 2010;12(7):665\u201375.","journal-title":"Nat Cell Biol"},{"issue":"1","key":"1346_CR40","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1186\/s12964-024-01734-3","volume":"22","author":"S Li","year":"2024","unstructured":"Li S, Ren W, Zheng J, Li S, Zhi K, Gao L. Role of O-linked N-acetylglucosamine protein modification in oxidative stress-induced autophagy: a novel target for bone remodeling. Cell Communication Signal. 2024;22(1):358.","journal-title":"Cell Communication Signal"},{"issue":"6","key":"1346_CR41","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1016\/j.joca.2015.03.031","volume":"23","author":"KB King","year":"2015","unstructured":"King KB, Rosenthal AK. The adverse effects of diabetes on osteoarthritis: update on clinical evidence and molecular mechanisms. Osteoarthr Cartil. 2015;23(6):841\u201350.","journal-title":"Osteoarthr Cartil"},{"issue":"6670","key":"1346_CR42","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1038\/36116","volume":"391","author":"DJ Withers","year":"1998","unstructured":"Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren J-M, Previs S, et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 1998;391(6670):900\u20134.","journal-title":"Nature"}],"container-title":["Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-025-01346-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10020-025-01346-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-025-01346-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T10:34:17Z","timestamp":1758882857000},"score":1,"resource":{"primary":{"URL":"https:\/\/molmed.biomedcentral.com\/articles\/10.1186\/s10020-025-01346-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,26]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1346"],"URL":"https:\/\/doi.org\/10.1186\/s10020-025-01346-8","relation":{},"ISSN":["1528-3658"],"issn-type":[{"value":"1528-3658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,26]]},"assertion":[{"value":"12 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The human and animal experiments conducted in this study have been reviewed and approved by the Ethics Committee of Nanjing First Hospital, Nanjing Medical University. Animal experiments were in accordance with the Institutional Animal Care and Use Committee of Nanjing Medical University on November 8, 2021 (approval no. DWSY-2101052). All animal experiments were performed in accordance with the Basel Declaration and \u201cGuide for The Care and Use of Laboratory Animals\u201d 8th Edition. The human tissue specimen experiments were approved by Ethics Committee of Nanjing First Hospital, Nanjing Medical University (no. KY20230918-KS-01), which was ratified on September 18, 2023. The local Ethics Committee follows the rules of Helsinki Declaration (human) and Basel Declaration (animals).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"293"}}