{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:06:52Z","timestamp":1792789612067,"version":"4.5.0"},"reference-count":55,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"First Affiliated Hospital of Harbin Medical University","award":["KYGQDJ2025119"],"award-info":[{"award-number":["KYGQDJ2025119"]}],"id":[{"id":"https:\/\/ror.org\/05vy2sc54","id-type":"ROR","asserted-by":"crossref"}]},{"award":["KYGQDJ2025119"],"award-info":[{"award-number":["KYGQDJ2025119"]}],"id":[{"id":"https:\/\/ror.org\/05vy2sc54","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Osteoarthritis (OA) is a chronic inflammatory and degenerative joint disease that commonly affects the aging population. This study was designed to decipher gene\u2013metabolite regulatory networks driving OA progression via combined computational prediction and experimental validation. Differential gene expression analysis, weighted gene coexpression network analysis, and machine learning algorithms were integrated to screen for key regulatory genes. To infer causal associations between these candidates and OA susceptibility, we performed Mendelian randomization (MR) using cis-expression quantitative trait loci (cis-eQTL) as genetic instruments and identified significant associations between TNFRSF10B and OA. In parallel, single-nucleus RNA sequencing (snRNA-seq) was used to map the cell-type-specific expression profile of TNFRSF10B, and its expression was validated in human knee synovial tissues. The protective effect of TNFRSF10B on OA was statistically mediated in part by the alpha-tocopherol-to-sulfate ratio, as inferred from Mendelian randomization analysis, with the indirect effect accounting for 16.85% (95% CI: 2.96\u201330.74%) of the total protective effect. snRNA-seq data revealed that TNFRSF10B was widely expressed across synovial cell populations but reduced in OA samples. Collectively, this study identified TNFRSF10B as a candidate protective factor in OA, supported by genetic evidence from MR analysis and reduced expression in OA synovial tissues, offering statistical evidence for gene\u2013metabolite interplay in OA pathogenesis.<\/jats:p>","DOI":"10.3390\/ijms27188382","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:32:12Z","timestamp":1790083932000},"page":"8382","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TNFRSF10B Implicated in Osteoarthritis Protection via the Alpha-Tocopherol-to-Sulfate Ratio: A Multiomics and Mendelian Randomization Study"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9522-847X","authenticated-orcid":false,"given":"Qichang","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Central Laboratory, First Affiliated Hospital of Harbin Medical University, Harbin 150081, China"},{"name":"Department of Pharmacology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Tuo","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Central Laboratory, First Affiliated Hospital of Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Yiming","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, First Affiliated Hospital of Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Zhange","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, First Affiliated Hospital of Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Jiaao","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, First Affiliated Hospital of Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2126-0876","authenticated-orcid":false,"given":"Keying","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Central Laboratory, First Affiliated Hospital of Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1002\/art.34453","article-title":"Osteoarthritis: A disease of the joint as an organ","volume":"64","author":"Loeser","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1397","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":"Osteoarthr. Cartil."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Rockel, J.S., Zhang, W., Shestopaloff, K., Likhodii, S., Sun, G., Furey, A., Randell, E., Sundararajan, K., Gandhi, R., and Zhai, G. (2018). A classification modeling approach for determining metabolite signatures in osteoarthritis. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199618"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"639","DOI":"10.3109\/1354750X.2016.1171907","article-title":"Plasma and synovial fluid inflammatory cytokine profiles in primary knee osteoarthritis","volume":"21","author":"Mabey","year":"2016","journal-title":"Biomarkers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.joca.2021.03.002","article-title":"Genetics of osteoarthritis","volume":"30","author":"Aubourg","year":"2022","journal-title":"Osteoarthr. Cartil."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100258","DOI":"10.1016\/j.ocarto.2022.100258","article-title":"Identification of a differential metabolite-based signature in patients with late-stage knee osteoarthritis","volume":"4","author":"Rockel","year":"2022","journal-title":"Osteoarthr. Cartil. Open"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1080\/07315724.1994.10718421","article-title":"The effect of folate and cobalamin on osteoarthritic hands","volume":"13","author":"Flynn","year":"1994","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1055\/s-0033-1334963","article-title":"B-vitamin mixture improves the analgesic effect of diclofenac in patients with osteoarthritis: A double blind study","volume":"63","year":"2013","journal-title":"Drug Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3899\/jrheum.200054","article-title":"Phenylalanine Is a Novel Marker for Radiographic Knee Osteoarthritis Progression: The MOST Study","volume":"48","author":"Zhai","year":"2021","journal-title":"J. Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.cca.2020.07.010","article-title":"Insight into osteoarthritis through integrative analysis of metabolomics and transcriptomics","volume":"510","author":"Huang","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.2147\/JIR.S504717","article-title":"Identification and Validation of Pivotal Genes in Osteoarthritis Combined with WGCNA Analysis","volume":"18","author":"Yang","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1080\/21691401.2025.2471762","article-title":"Unveiling the ageing-related genes in diagnosing osteoarthritis with metabolic syndrome by integrated bioinformatics analysis and machine learning","volume":"53","author":"Huang","year":"2025","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1080\/21691401.2024.2318210","article-title":"Comprehensive analysis of anoikis-related genes in diagnosis osteoarthritis: Based on machine learning and single-cell RNA sequencing data","volume":"52","author":"Zhang","year":"2024","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1001\/jama.2017.17219","article-title":"Mendelian Randomization","volume":"318","author":"Emdin","year":"2017","journal-title":"JAMA"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Pang, W.W., Cai, Y.S., Cao, C., Zhang, F.R., Zeng, Q., Liu, D.Y., Wang, N., Qu, X.C., Chen, X.D., and Deng, H.W. (2024). Mendelian randomization and transcriptome analysis identified immune-related biomarkers for osteoarthritis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1334479"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"156625","DOI":"10.1016\/j.cyto.2024.156625","article-title":"Circulating cytokines levels and osteoarthritis: A Mendelian randomization study","volume":"179","author":"Xie","year":"2024","journal-title":"Cytokine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eadf4590","DOI":"10.1126\/scitranslmed.adf4590","article-title":"Single-cell atlas of human infrapatellar fat pad and synovium implicates APOE signaling in osteoarthritis pathology","volume":"16","author":"Tang","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.7150\/ijms.111848","article-title":"Deciphering the Relationship Between Circulating Metabolites and Osteoarthritis: A Comprehensive Genetic Correlation and Mendelian Randomization Studies","volume":"22","author":"Yang","year":"2025","journal-title":"Int. J. Med. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"305","DOI":"10.4103\/npmj.npmj_187_25","article-title":"Mendelian Randomisation Uncovers Causal Immune-Metabolic Networks in Osteoarthritis: Insights from Immune Cell and Metabolite Interactions","volume":"32","author":"Chen","year":"2025","journal-title":"Niger. Postgrad. Med. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s13018-025-06604-3","article-title":"Integrative multi-omics analysis reveals gut microbiota-derived metabolites and immune regulatory pathways in osteoarthritis pathogenesis","volume":"21","author":"Wang","year":"2026","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chen, Y., Lin, J., Shi, D., Miao, Y., Xue, F., Liu, K., Wang, X., and Zhang, C. (2025). Identification of WDR74 and TNFRSF12A as biomarkers for early osteoarthritis using machine learning and immunohistochemistry. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1517646"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"156300","DOI":"10.1016\/j.cyto.2023.156300","article-title":"Identification of four-gene signature to diagnose osteoarthritis through bioinformatics and machine learning methods","volume":"169","author":"Chen","year":"2023","journal-title":"Cytokine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s12944-024-02073-5","article-title":"Identification and validation of biomarkers related to lipid metabolism in osteoarthritis based on machine learning algorithms","volume":"23","author":"Li","year":"2024","journal-title":"Lipids Health Dis."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wu, Y., Hu, H., Wang, T., Guo, W., Zhao, S., and Wei, R. (2024). Characterizing mitochondrial features in osteoarthritis through integrative multi-omics and machine learning analysis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1414301"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/ng1097-141","article-title":"KILLER\/DR5 is a DNA damage-inducible p53-regulated death receptor gene","volume":"17","author":"Wu","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Trivedi, R., and Mishra, D.P. (2015). Trailing TRAIL Resistance: Novel Targets for TRAIL Sensitization in Cancer Cells. Front. Oncol., 5.","DOI":"10.3389\/fonc.2015.00069"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1038\/s41375-023-02035-3","article-title":"del(8p) and TNFRSF10B loss are associated with a poor prognosis and resistance to fludarabine in chronic lymphocytic leukemia","volume":"37","author":"Jondreville","year":"2023","journal-title":"Leukemia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6392","DOI":"10.1038\/s41598-021-85589-5","article-title":"Death agonist antibody against TRAILR2\/DR5\/TNFRSF10B enhances birinapant anti-tumor activity in HPV-positive head and neck squamous cell carcinomas","volume":"11","author":"An","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S1359-6101(02)00006-0","article-title":"On the TRAIL to apoptosis","volume":"13","author":"Baetu","year":"2002","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.4049\/jimmunol.171.2.1061","article-title":"TRAIL-R2 (DR5) mediates apoptosis of synovial fibroblasts in rheumatoid arthritis","volume":"171","author":"Ichikawa","year":"2003","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e48840","DOI":"10.7554\/eLife.48840","article-title":"Soluble Fas ligand drives autoantibody-induced arthritis by binding to DR5\/TRAIL-R2","volume":"10","author":"Jeong","year":"2021","journal-title":"eLife"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/imm.12181","article-title":"TRAIL receptor deficiency sensitizes mice to dextran sodium sulphate-induced colitis and colitis-associated carcinogenesis","volume":"141","author":"Zhu","year":"2014","journal-title":"Immunology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"102249","DOI":"10.1016\/j.jchemneu.2023.102249","article-title":"TNFRSF10B is involved in motor dysfunction in Parkinson\u2019s disease by regulating exosomal \u03b1-synuclein secretion from microglia","volume":"129","author":"Dai","year":"2023","journal-title":"J. Chem. Neuroanat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.jpba.2016.01.056","article-title":"Analytical strategies to assess the functional metabolome of vitamin E","volume":"124","author":"Torquato","year":"2016","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.freeradbiomed.2012.09.012","article-title":"Urinary conjugated \u03b1-tocopheronolactone--a biomarker of oxidative stress in children with type 1 diabetes","volume":"55","author":"Sharma","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/BF03179812","article-title":"Vitamin E: Action, metabolism and perspectives","volume":"57","author":"Herrera","year":"2001","journal-title":"J. Physiol. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/iub.1988","article-title":"Vitamin E: Regulatory role of metabolites","volume":"71","author":"Birringer","year":"2019","journal-title":"IUBMB Life"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.freeradbiomed.2016.09.017","article-title":"Vitamin E: Emerging aspects and new directions","volume":"102","author":"Galli","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4192","DOI":"10.1016\/j.clnu.2021.01.039","article-title":"Urinary oxidized, but not enzymatic vitamin E metabolites are inversely associated with measures of glucose homeostasis in middle-aged healthy individuals","volume":"40","author":"Luo","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1093\/aje\/kwh133","article-title":"A case-control study of serum tocopherol levels and the alpha- to gamma-tocopherol ratio in radiographic knee osteoarthritis: The Johnston County Osteoarthritis Project","volume":"159","author":"Jordan","year":"2004","journal-title":"Am. J. Epidemiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1111\/j.1756-185X.2009.01430.x","article-title":"Lipid peroxidation, glutathione, vitamin E, and antioxidant enzymes in synovial fluid from patients with osteoarthritis","volume":"12","author":"Sutipornpalangkul","year":"2009","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"236","DOI":"10.3109\/14397595.2013.854055","article-title":"Association of dietary intake with joint space narrowing and osteophytosis at the knee in Japanese men and women: The ROAD study","volume":"24","author":"Muraki","year":"2014","journal-title":"Mod. Rheumatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"20069","DOI":"10.1074\/jbc.M907604199","article-title":"Evidence linking chondrocyte lipid peroxidation to cartilage matrix protein degradation. Possible role in cartilage aging and the pathogenesis of osteoarthritis","volume":"275","author":"Tiku","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s00011-013-0635-y","article-title":"Vitamin E protects chondrocytes against hydrogen peroxide-induced oxidative stress in vitro","volume":"62","author":"Bhatti","year":"2013","journal-title":"Inflamm. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1006\/cbir.1999.0424","article-title":"Reactive oxygen species induce apoptosis of synoviocytes in vitro. Alpha-tocopherol provides no protection","volume":"23","author":"Galleron","year":"1999","journal-title":"Cell Biol. Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.3390\/nu6041424","article-title":"The effects of \u03b1-tocopherol on bone: A double-edged sword?","volume":"6","author":"Chin","year":"2014","journal-title":"Nutrients"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.joca.2025.08.013","article-title":"Cross-platform transcriptomic data integration identifies an overactive neuro-immune signature in human osteoarthritis synovium","volume":"34","author":"Newton","year":"2026","journal-title":"Osteoarthr. Cartil."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e238","DOI":"10.1002\/imt2.238","article-title":"Sangerbox 2: Enhanced functionalities and update for a comprehensive clinical bioinformatics data analysis platform","volume":"3","author":"Chen","year":"2024","journal-title":"iMeta"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"The Gene Ontology Consortium (2015). Gene Ontology Consortium: Going forward. Nucleic Acids Res., 43, D1049\u2013D1056.","DOI":"10.1093\/nar\/gku1179"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Langfelder, P., and Horvath, S. (2008). WGCNA: An R package for weighted correlation network analysis. BMC Bioinform., 9.","DOI":"10.1186\/1471-2105-9-559"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1093\/bioinformatics\/btq170","article-title":"ConsensusClusterPlus: A class discovery tool with confidence assessments and item tracking","volume":"26","author":"Wilkerson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12931-025-03124-w","article-title":"HMOX1 as a potential drug target for upper and lower airway diseases: Insights from multi-omics analysis","volume":"26","author":"Wang","year":"2025","journal-title":"Respir. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e095098","DOI":"10.1136\/bmjopen-2024-095098","article-title":"Relationship between sleep characteristics and aortic aneurysm\/dissection: A two-sample Mendelian randomisation study","volume":"15","author":"Zeng","year":"2025","journal-title":"BMJ Open"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s12944-023-01877-1","article-title":"Low-density lipoprotein cholesterol and risk of hepatocellular carcinoma: A Mendelian randomization and mediation analysis","volume":"22","author":"Cao","year":"2023","journal-title":"Lipids Health Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8382\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:33:36Z","timestamp":1790094816000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8382"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,20]]},"references-count":55,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27188382"],"URL":"https:\/\/doi.org\/10.3390\/ijms27188382","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,20]]}}}