{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:28:14Z","timestamp":1785414494320,"version":"3.56.0"},"reference-count":58,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82400667"],"award-info":[{"award-number":["82400667"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82400667"],"award-info":[{"award-number":["82400667"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disorder driven by genetic predisposition, epigenetic programming, metabolic rewiring, and immune dysregulation. Although population genetics and single-cell transcriptomics have advanced our understanding, the multi-omic causal architecture of MASLD at cellular resolution remains poorly defined. This study aimed to establish an integrative framework linking genetic causality to cell-type-specific tissue dysfunction. Methods: Multi-layered Mendelian randomization (MR) and summary-data-based MR (SMR) across large-scale eQTL and pQTL datasets were applied to prioritize causal genes. Single-cell eQTL-based MR across 14 immune lineages generated cell-type-specific causal hypotheses, which were validated using human hepatic single-cell RNA-sequencing data (GSE136103). Two-step mediation MR quantified upstream epigenetic and downstream metabolic mechanisms. A high-fat diet (HFD)-induced murine model provided organismal validation. Results: Multi-layered MR nominated PLXND1 as a robust causal driver of MASLD. Single-cell eQTL-based MR revealed a functional dichotomy: PLXND1 upregulation in CD8+ effector memory T-cells decreased MASLD risk (OR = 0.486, 95% CI: 0.290\u20130.813, p = 0.006), whereas upregulation in natural killer cells (OR = 1.567, 95% CI: 1.337\u20131.837, p &lt; 0.001), non-classical monocytes, and dendritic cells increased risk. Human hepatic single-cell transcriptomics confirmed that PLXND1 marks an anti-fibrotic, IFNG-high CD8+ T subset and a pro-inflammatory lipid-associated macrophage (LAM) population. Mediation MR identified DNA methylation at cg26767922 and cg08471739 as protective mediators acting predominantly via PLXND1 downregulation (92.39% and 64.50% mediation, respectively), and linked PLXND1 to six circulating metabolites. HFD mice showed significant hepatic PLXND1 upregulation. Conclusions:PLXND1 functions as a lineage-dependent molecular switch in MASLD, validated across genetic, epigenetic, metabolic, and single-cell dimensions. These findings caution against systemic PLXND1 blockade and support precision therapeutic strategies targeting hepatic innate immune cells.<\/jats:p>","DOI":"10.3390\/metabo16060378","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T17:11:01Z","timestamp":1780333861000},"page":"378","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetically Informed Single-Cell Analysis Reveals PLXND1 as a Cell-Type-Specific Molecular Switch in MASLD"],"prefix":"10.3390","volume":"16","author":[{"given":"Xianyi","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junbo","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41575-021-00523-4","article-title":"Advancing the global public health agenda for NAFLD: A consensus statement","volume":"19","author":"Lazarus","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/S2468-1253(22)00165-0","article-title":"The prevalence and incidence of NAFLD worldwide: A systematic review and meta-analysis","volume":"7","author":"Riazi","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.jhep.2023.06.003","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"79","author":"Rinella","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/s41575-024-00990-5","article-title":"MASLD: A disease in flux","volume":"21","author":"Allen","year":"2024","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.tem.2024.02.007","article-title":"Current status and future trends of the global burden of MASLD","volume":"35","author":"Miao","year":"2024","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.jhep.2023.01.026","article-title":"Healthcare and socioeconomic costs of NAFLD: A global framework to navigate the uncertainties","volume":"79","author":"Allen","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/s41571-023-00825-3","article-title":"Global trends in hepatocellular carcinoma epidemiology: Implications for screening, prevention and therapy","volume":"20","author":"Singal","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/s41575-023-00754-7","article-title":"Nonalcoholic steatohepatitis-related hepatocellular carcinoma: Pathogenesis and treatment","volume":"20","author":"Llovet","year":"2023","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41575-025-01039-x","article-title":"MASLD as a non-communicable disease","volume":"22","author":"Sookoian","year":"2025","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/s41575-025-01045-z","article-title":"\u039cetabolic dysfunction-associated steatotic liver disease: A condition of heterogeneous metabolic risk factors, mechanisms and comorbidities requiring holistic treatment","volume":"22","author":"Byrne","year":"2025","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/S2468-1253(23)00159-0","article-title":"NASH drug treatment development: Challenges and lessons","volume":"8","author":"Tilg","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/s41591-023-02242-6","article-title":"Challenges and opportunities in NASH drug development","volume":"29","author":"Harrison","year":"2023","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1056\/NEJMoa2309000","article-title":"A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis","volume":"390","author":"Harrison","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.jhep.2023.02.033","article-title":"Role of immune responses in the development of NAFLD-associated liver cancer and prospects for therapeutic modulation","volume":"79","author":"Yahoo","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1093\/cvr\/cvad095","article-title":"Non-alcoholic fatty liver disease: Pathophysiological concepts and treatment options","volume":"119","author":"Grander","year":"2023","journal-title":"Cardiovasc. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s41392-023-01333-7","article-title":"Epigenetic regulation in metabolic diseases: Mechanisms and advances in clinical study","volume":"8","author":"Wu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_18","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_19","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_20","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/hep.32534","article-title":"Relationship between NAFLD and coronary artery disease: A Mendelian randomization study","volume":"77","author":"Ren","year":"2023","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/s41591-021-01310-z","article-title":"Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19","volume":"27","author":"Gaziano","year":"2021","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1126\/science.aaz1776","article-title":"The GTEx Consortium atlas of genetic regulatory effects across human tissues","volume":"369","author":"Center","year":"2020","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/s41562-024-02040-1","article-title":"A multi-omics Mendelian randomization study identifies new therapeutic targets for alcohol use disorder and problem drinking","volume":"9","author":"Rosoff","year":"2025","journal-title":"Nat. Hum. Behav."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1136\/gutjnl-2024-332398","article-title":"Interplay between gut microbiome, host genetic and epigenetic modifications in MASLD and MASLD-related hepatocellular carcinoma","volume":"74","author":"Ha","year":"2024","journal-title":"Gut"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13059-016-0926-z","article-title":"Systematic identification of genetic influences on methylation across the human life course","volume":"17","author":"Gaunt","year":"2016","journal-title":"Genome Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1038\/s41588-022-01199-5","article-title":"Multiomics study of nonalcoholic fatty liver disease","volume":"54","author":"Sveinbjornsson","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.jhep.2022.06.012","article-title":"Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease\u2014Novel insights into cellular communication circuits","volume":"77","author":"Peiseler","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100341","DOI":"10.1016\/j.xgen.2023.100341","article-title":"Multi-layered genetic approaches to identify approved drug targets","volume":"3","author":"Sadler","year":"2023","journal-title":"Cell Genom."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eabf3041","DOI":"10.1126\/science.abf3041","article-title":"Single-cell eQTL mapping identifies cell type-specific genetic control of autoimmune disease","volume":"376","author":"Yazar","year":"2022","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/s41586-020-1979-4","article-title":"The guidance receptor plexin D1 is a mechanosensor in endothelial cells","volume":"578","author":"Mehta","year":"2020","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1038\/s41588-021-00913-z","article-title":"Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression","volume":"53","author":"Claringbould","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1038\/s41588-021-00978-w","article-title":"Large-scale integration of the plasma proteome with genetics and disease","volume":"53","author":"Ferkingstad","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"105596","DOI":"10.1016\/j.ebiom.2025.105596","article-title":"Single-cell transcriptome-wide Mendelian randomization and colocalization reveals immune-mediated regulatory mechanisms and drug targets for COVID-19","volume":"113","author":"Ying","year":"2025","journal-title":"EBioMedicine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1038\/s41588-021-00923-x","article-title":"Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation","volume":"53","author":"Min","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1002\/hep.32728","article-title":"The associations between modifiable risk factors and nonalcoholic fatty liver disease: A comprehensive Mendelian randomization study","volume":"77","author":"Xie","year":"2023","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.jhep.2024.09.033","article-title":"Association of metabolic signatures of air pollution with MASLD: Observational and Mendelian randomization study","volume":"82","author":"Ran","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/s41586-023-06563-x","article-title":"Large-scale plasma proteomics comparisons through genetics and disease associations","volume":"622","author":"Eldjarn","year":"2023","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1097\/JS9.0000000000003576","article-title":"Decoding the triglyceride-glucose index in metabolic dysfunction-associated steatotic liver disease: Integrative insights from Mendelian randomization, cross-tissue transcriptomics, and spatial multi-omics","volume":"112","author":"Wei","year":"2026","journal-title":"Int. J. Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e22601","DOI":"10.1002\/gepi.22601","article-title":"Integrative Multi-Omics Approach for Improving Causal Gene Identification","volume":"49","author":"King","year":"2025","journal-title":"Genet. Epidemiol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Bourganou, M.V., Chondrogianni, M.E., Kyrou, I., Flessa, C.M., Chatzigeorgiou, A., Oikonomou, E., Lambadiari, V., Randeva, H.S., and Kassi, E. (2025). Unraveling Metabolic Dysfunction-Associated Steatotic Liver Disease Through the Use of Omics Technologies. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202501.0541.v1"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1038\/s41588-025-02407-8","article-title":"Spatially resolved multi-omics of human metabolic dysfunction-associated steatotic liver disease","volume":"57","author":"Li","year":"2025","journal-title":"Nat. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/s41746-026-02352-8","article-title":"Integrating multi-omics and machine learning systematically deciphers cellular heterogeneity and fibrotic regulatory networks in the progression from MASLD to MASH","volume":"9","author":"Wen","year":"2026","journal-title":"NPJ Digit. Med."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Barchetta, I., Zampieri, M., Cimini, F.A., Dule, S., Sentinelli, F., Passarella, G., Oldani, A., Karpach, K., Bacalini, M.G., and Baroni, M.G. (2025). Association Between Active DNA Demethylation and Liver Fibrosis in Individuals with Metabolic-Associated Steatotic Liver Disease (MASLD). Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26031271"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"eaba4448","DOI":"10.1126\/scitranslmed.aba4448","article-title":"Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis","volume":"12","author":"Govaere","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"eaeb5665","DOI":"10.1126\/sciadv.aeb5665","article-title":"Cross-trait genomic modeling reveals the polygenic architecture and systemic impact of MASLD","volume":"12","author":"Du","year":"2026","journal-title":"Sci. Adv."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/s41588-022-01078-z","article-title":"A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation","volume":"54","author":"Vujkovic","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1172\/JCI186421","article-title":"Dissecting the mechanisms of MASLD fibrosis in the era of single-cell and spatial omics","volume":"135","author":"Colella","year":"2025","journal-title":"J. Clin. Invest."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1038\/s41590-025-02255-y","article-title":"Single-cell atlas of human liver and blood immune cells across fatty liver disease stages reveals distinct signatures linked to liver dysfunction and fibrogenesis","volume":"26","author":"Martin","year":"2025","journal-title":"Nat. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"105232","DOI":"10.1016\/j.ebiom.2024.105232","article-title":"Single nucleus RNA-sequencing integrated into risk variant colocalization discovers 17 cell-type-specific abdominal obesity genes for metabolic dysfunction-associated steatotic liver disease","volume":"106","author":"Lee","year":"2024","journal-title":"EBioMedicine"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"eabf1970","DOI":"10.1126\/science.abf1970","article-title":"Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus","volume":"376","author":"Perez","year":"2022","journal-title":"Science"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1126\/science.1105416","article-title":"Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins","volume":"307","author":"Gu","year":"2005","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.cmet.2013.09.001","article-title":"Semaphorin3E-induced inflammation contributes to insulin resistance in dietary obesity","volume":"18","author":"Shimizu","year":"2013","journal-title":"Cell Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/j.immuni.2020.04.001","article-title":"Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis","volume":"52","author":"Seidman","year":"2020","journal-title":"Immunity"},{"key":"ref_54","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_55","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.immuni.2020.08.004","article-title":"Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver","volume":"53","author":"Remmerie","year":"2020","journal-title":"Immunity"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.immuni.2008.10.008","article-title":"PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla","volume":"29","author":"Choi","year":"2008","journal-title":"Immunity"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1097\/HEP.0000000000000407","article-title":"Semaphorin 3C exacerbates liver fibrosis","volume":"78","author":"Wiedmann","year":"2023","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s41586-021-03233-8","article-title":"Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH","volume":"592","author":"Dudek","year":"2021","journal-title":"Nature"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/6\/378\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T17:28:11Z","timestamp":1780334891000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/6\/378"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,30]]},"references-count":58,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["metabo16060378"],"URL":"https:\/\/doi.org\/10.3390\/metabo16060378","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,30]]}}}