{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:09:16Z","timestamp":1785431356006,"version":"3.56.0"},"reference-count":66,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002767","name":"Department of Science and Technology of Hunan Province","doi-asserted-by":"publisher","award":["2024JJ6342"],"award-info":[{"award-number":["2024JJ6342"]}],"id":[{"id":"10.13039\/501100002767","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2024JJ6342"],"award-info":[{"award-number":["2024JJ6342"]}],"id":[{"id":"https:\/\/ror.org\/04qgr7x96","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD) and osteoporosis (OP) are epidemiologically linked, but shared cell-type-specific molecular features remain unclear. We integrated public single-cell\/single-nucleus transcriptomic datasets for OP (GSE147287) and MASLD (GSE289173) with two-sample Mendelian randomization (MR), colocalization, network annotation, macrophage-focused in silico perturbation, and exploratory serum assessment. After quality control, 13,753 OP cells and 42,438 MASLD cells\/nuclei were analyzed. Macrophages were consistently identified in both datasets and showed disease-associated expansion. Directionally concordant macrophage differentially expressed genes yielded 147 shared candidate genes, with enrichment mainly involving lipid\/sterol metabolism, extracellular matrix and adhesion processes, immune presentation, lysosomal processing, and phagocytic pathways. MR prioritized MUC20 as the only candidate with concordant odds ratios greater than 1 for both OP (OR = 1.044, 95% CI 1.003\u20131.086) and MASLD (OR = 1.111, 95% CI 1.038\u20131.189). Colocalization supported shared genetic signals for MUC20 in OP (PP.H4 = 0.855) and MASLD (PP.H4 = 0.816). In silico perturbation suggested a limited but pathway-enriched predicted transcriptional footprint. Serum MUC20 was higher in patients with OP+MASLD than in healthy controls. This integrative analysis identified shared macrophage-associated transcriptional themes and prioritized MUC20 as a candidate molecule for future liver\u2013bone crosstalk studies.<\/jats:p>","DOI":"10.3390\/ijms27125453","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T03:27:21Z","timestamp":1781666841000},"page":"5453","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Single-Cell Transcriptomic, Mendelian Randomization and In Silico Perturbation Analyses Prioritize MUC20 as a Candidate Gene Associated with Osteoporosis and Metabolic Dysfunction-Associated Steatotic Liver Disease in the Liver\u2013Bone Axis"],"prefix":"10.3390","volume":"27","author":[{"given":"Hui","family":"Jin","sequence":"first","affiliation":[{"name":"School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"},{"name":"Graduate School, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangting","family":"Ye","sequence":"additional","affiliation":[{"name":"Graduate School, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonghui","family":"Jian","sequence":"additional","affiliation":[{"name":"School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xiong","sequence":"additional","affiliation":[{"name":"School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/S2468-1253(22)00317-X","article-title":"Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: A systematic review and meta-analysis","volume":"8","author":"Quek","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1016\/j.cgh.2021.12.002","article-title":"2019 Global NAFLD Prevalence: A Systematic Review and Meta-analysis","volume":"20","author":"Le","year":"2022","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Castagna, A., Pujia, C., Mazza, E., Maurotti, S., Ferro, Y., Rizzo, V., Formica, M., Conforto, R., Mercuri, C., and Sciacqua, A. (2026). Underlying Mechanisms of Osteoporosis in the Context of Multimorbidity: Clinical Challenges and Management Strategies. Nutrients, 18.","DOI":"10.3390\/nu18020262"},{"key":"ref_4","unstructured":"GBD 2019 Fracture Collaborators (2021). Global, regional, and national burden of bone fractures in 204 countries and territories, 1990\u20132019: A systematic analysis from the Global Burden of Disease Study 2019. Lancet Healthy Longev., 2, e580\u2013e592."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Li, X., Luo, W., Chen, K., and Peng, Y. (2025). Association of metabolic dysfunction-associated steatotic liver disease with bone health in adults: A systematic review and meta-analysis of observational studies. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1717852"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1007\/s00198-022-06459-y","article-title":"Relationship between prevalence and risk of osteoporosis or osteoporotic fracture with non-alcoholic fatty liver disease: A systematic review and meta-analysis","volume":"33","author":"Pan","year":"2022","journal-title":"Osteoporos. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101785","DOI":"10.1016\/j.bonr.2024.101785","article-title":"Association between nonalcoholic fatty liver disease and bone mineral density: Mendelian randomization and mediation analysis","volume":"22","author":"Zheng","year":"2024","journal-title":"Bone Rep."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Alabdulaali, B., Al-Rashed, F., Al-Onaizi, M., Kandari, A., Razafiarison, J., Tonui, D., Williams, M.R., Bl\u00e9riot, C., Ahmad, R., and Alzaid, F. (2023). Macrophages and the development and progression of non-alcoholic fatty liver disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1195699"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhang, W., and Lang, R. (2023). Macrophage metabolism in nonalcoholic fatty liver disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1257596"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1002\/jbmr.4773","article-title":"Macrophages and Bone Remodeling","volume":"38","author":"Weivoda","year":"2023","journal-title":"J. Bone Miner. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/prd.12519","article-title":"Osteoinduction and osteoimmunology: Emerging concepts","volume":"94","author":"Miron","year":"2000","journal-title":"Periodontology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11914-025-00949-8","article-title":"Advances in Spatial Transcriptomics in Bone","volume":"24","author":"Giger","year":"2026","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Abo Nahas, H.H., Al-Dakhil, A., Mohamed, D.I., Yousef, T.A., Almaaty, A.H.A., El-Deen, I.M., Sembawa, H.A.M., and Saied, E.M. (2026). Rebamipide Reprograms Hepatic Networks to Prevent and Reverse Metabolic-Dysfunction-Associated Steatotic Liver Disease: Multi-Omics Insights and Histological Validation. Pharmaceuticals, 19.","DOI":"10.3390\/ph19040559"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1001\/jama.2021.18236","article-title":"Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement","volume":"326","author":"Skrivankova","year":"2021","journal-title":"JAMA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"D870","DOI":"10.1093\/nar\/gkac947","article-title":"CellMarker 2.0: An updated database of manually curated cell markers in human\/mouse and web tools based on scRNA-seq data","volume":"51","author":"Hu","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s00774-016-0807-2","article-title":"Nonalcoholic fatty liver disease and osteoporosis: A systematic review and meta-analysis","volume":"35","author":"Upala","year":"2017","journal-title":"J. Bone Miner. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1007\/s12672-025-03582-0","article-title":"Mendelian randomization analysis reveals no causal association between non-alcoholic fatty liver disease and hepatocellular carcinoma: Implications for lipid metabolomics and shared pathophysiological mechanisms","volume":"16","author":"Wei","year":"2025","journal-title":"Discov. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chen, J., Zhou, H., Jin, H., and Liu, K. (2022). Role of Inflammatory Factors in Mediating the Effect of Lipids on Nonalcoholic Fatty Liver Disease: A Two-Step, Multivariable Mendelian Randomization Study. Nutrients, 14.","DOI":"10.3390\/nu14204434"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1152\/physrev.00034.2024","article-title":"Immunomodulatory properties of transmembrane mucins: From chronic diseases to cancer","volume":"105","author":"Montero","year":"2025","journal-title":"Physiol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, W., Li, S., Liu, Y., Ding, X., Yang, Y., Chen, S., Cao, J., Tacke, F., Dong, W., and Lan, T. (2025). Macrophage heterogeneity in liver fibrosis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1639455"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2405746121","DOI":"10.1073\/pnas.2405746121","article-title":"Lipid-associated macrophages\u2019 promotion of fibrosis resolution during MASH regression requires TREM2","volume":"121","author":"Ganguly","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/978-1-0716-2128-8_15","article-title":"Single Cell RNA Sequencing in NASH","volume":"2455","author":"Hundertmark","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"eadj3289","DOI":"10.1126\/sciadv.adj3289","article-title":"Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis","volume":"10","author":"Wang","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e12824","DOI":"10.1111\/cmi.12824","article-title":"Lysosome remodelling and adaptation during phagocyte activation","volume":"20","author":"Hipolito","year":"2018","journal-title":"Cell. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.immuni.2020.06.003","article-title":"Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis","volume":"53","author":"Tran","year":"2020","journal-title":"Immunity"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kannan, R., Carruthers, N.J., Koh, A.J., Kleer, G.G., Nakamura, K., Parker, S.C.J., McCauley, L.K., and Roca, H. (2025). Efferocytosis-induced metabolic shift in bone macrophages drives lactate production and modulates inflammation and osteoclastogenesis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1650465"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12018-023-09286-9","article-title":"The Macrophage\u2019s Role on Bone Remodeling and Osteogenesis: A Systematic Review","volume":"21","author":"Orvalho","year":"2023","journal-title":"Clin. Rev. Bone Miner. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2214","DOI":"10.1002\/jbmr.4413","article-title":"Osteal macrophages support osteoclast-mediated resorption and contribute to bone pathology in a postmenopausal osteoporosis mouse model","volume":"36","author":"Batoon","year":"2021","journal-title":"J. Bone Miner. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41592-021-01336-8","article-title":"Benchmarking atlas-level data integration in single-cell genomics","volume":"19","author":"Luecken","year":"2022","journal-title":"Nat. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13059-019-1850-9","article-title":"A benchmark of batch-effect correction methods for single-cell RNA sequencing data","volume":"21","author":"Tran","year":"2020","journal-title":"Genome Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Ni, Y., Wang, Z., Prud\u2019homme, G.J., and Wang, Q. (2023). Causal effects of non-alcoholic fatty liver disease on osteoporosis: A Mendelian randomization study. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1283739"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"n2233","DOI":"10.1136\/bmj.n2233","article-title":"Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): Explanation and elaboration","volume":"375","author":"Skrivankova","year":"2021","journal-title":"BMJ"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100434","DOI":"10.1016\/j.patter.2022.100434","article-title":"scTenifoldKnk: An efficient virtual knockout tool for gene function predictions via single-cell gene regulatory network perturbation","volume":"3","author":"Osorio","year":"2022","journal-title":"Patterns"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1038\/s41586-022-05688-9","article-title":"Dissecting cell identity via network inference and in silico gene perturbation","volume":"614","author":"Kamimoto","year":"2023","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Ye, W., Wang, Y.D., and Chen, W.D. (2022). HGF\/c-Met: A Key Promoter in Liver Regeneration. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.808855"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13046-024-02972-6","article-title":"MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis","volume":"43","author":"Wang","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_40","first-page":"695","article-title":"MUC20 as a novel prognostic biomarker in ccRCC correlating with tumor immune microenvironment modulation","volume":"12","author":"Xue","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1007\/s10120-022-01283-z","article-title":"Intracellular MUC20 variant 2 maintains mitochondrial calcium homeostasis and enhances drug resistance in gastric cancer","volume":"25","author":"Fu","year":"2022","journal-title":"Gastric Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6132","DOI":"10.1167\/iovs.14-15269","article-title":"Expression analysis of the transmembrane mucin MUC20 in human corneal and conjunctival epithelia","volume":"55","author":"Woodward","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e31403","DOI":"10.1016\/j.heliyon.2024.e31403","article-title":"Prognostic role of MUCIN family and its relationship with immune characteristics and tumor biology in diffuse-type gastric cancer","volume":"10","author":"Luo","year":"2024","journal-title":"Heliyon"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1002\/jbmr.4862","article-title":"Nonalcoholic Fatty Liver Disease Is Associated With Decreased Bone Mineral Density in Adults: A Systematic Review and Meta-Analysis","volume":"38","author":"Su","year":"2023","journal-title":"J. Bone Miner. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6041","DOI":"10.1038\/s41388-018-0403-0","article-title":"Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF\/MET pathway","volume":"37","author":"Chen","year":"2018","journal-title":"Oncogene"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"108","DOI":"10.7570\/jomes24004","article-title":"Effects of Metabolic Dysfunction-Associated Steatotic Liver Disease on Bone Density and Fragility Fractures: Associations and Mechanisms","volume":"33","author":"Khanmohammadi","year":"2024","journal-title":"J. Obes. Metab. Syndr."},{"key":"ref_47","first-page":"217","article-title":"Emerging role of liver-bone axis in osteoporosis","volume":"48","author":"Gao","year":"2024","journal-title":"J. Orthop. Transl."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.cmet.2015.09.010","article-title":"A Liver-Bone Endocrine Relay by IGFBP1 Promotes Osteoclastogenesis and Mediates FGF21-Induced Bone Resorption","volume":"22","author":"Wang","year":"2015","journal-title":"Cell Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"D1257","DOI":"10.1093\/nar\/gkac833","article-title":"Comparative Toxicogenomics Database (CTD): Update 2023","volume":"51","author":"Davis","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.3390\/jox14030057","article-title":"Incorporating Tissue-Specific Gene Expression Data to Improve Chemical-Disease Inference of in Silico Toxicogenomics Methods","volume":"14","author":"Wang","year":"2024","journal-title":"J. Xenobiotics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1038\/s41467-018-05116-5","article-title":"Network-based approach to prediction and population-based validation of in silico drug repurposing","volume":"9","author":"Cheng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"152244","DOI":"10.1016\/j.aanat.2024.152244","article-title":"OsteoMac: A new player on the bone biology scene","volume":"254","author":"Tresguerres","year":"2024","journal-title":"Ann. Anat.-Anat. Anz."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5692","DOI":"10.1038\/s41467-021-25960-2","article-title":"Confronting false discoveries in single-cell differential expression","volume":"12","author":"Squair","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"D138","DOI":"10.1093\/nar\/gkad965","article-title":"NCBI GEO: Archive for gene expression and epigenomics data sets: 23-year update","volume":"52","author":"Clough","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4192","DOI":"10.7150\/ijbs.61950","article-title":"Single-cell RNA sequencing deconvolutes the in vivo heterogeneity of human bone marrow-derived mesenchymal stem cells","volume":"17","author":"Wang","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1038\/s41588-025-02237-8","article-title":"Single-cell eQTL analysis identifies genetic variation underlying metabolic dysfunction-associated steatohepatitis","volume":"57","author":"Hong","year":"2025","journal-title":"Nat. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s43586-021-00092-5","article-title":"Mendelian randomization","volume":"2","author":"Sanderson","year":"2022","journal-title":"Nat. Rev. Methods Primers"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1038\/s41588-021-00924-w","article-title":"A compendium of uniformly processed human gene expression and splicing quantitative trait loci","volume":"53","author":"Kerimov","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Kerimov, N., Tambets, R., Hayhurst, J.D., Rahu, I., Kolberg, P., Raudvere, U., Kuzmin, I., Chowdhary, A., Vija, A., and Teras, H.J. (2023). eQTL Catalogue 2023: New datasets, X chromosome QTLs, and improved detection and visualisation of transcript-level QTLs. PLoS Genet., 19.","DOI":"10.1371\/journal.pgen.1010932"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1093\/ije\/dyad018","article-title":"Design and quality control of large-scale two-sample Mendelian randomization studies","volume":"52","author":"Haycock","year":"2023","journal-title":"Int. J. Epidemiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_63","first-page":"100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"iyad031","DOI":"10.1093\/genetics\/iyad031","article-title":"The Gene Ontology knowledgebase in 2023","volume":"224","author":"Aleksander","year":"2023","journal-title":"Genetics"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"D587","DOI":"10.1093\/nar\/gkac963","article-title":"KEGG for taxonomy-based analysis of pathways and genomes","volume":"51","author":"Kanehisa","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"D222","DOI":"10.1093\/nar\/gkab1079","article-title":"miRTarBase update 2022: An informative resource for experimentally validated miRNA-target interactions","volume":"50","author":"Huang","year":"2022","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5453\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:47:39Z","timestamp":1781844459000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5453"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,16]]},"references-count":66,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125453"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125453","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,16]]}}}