{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:18:39Z","timestamp":1790360319809,"version":"4.1.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"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","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Autoimmune thyroiditis (AIT), a prevalent autoimmune disorder that frequently leads to hypothyroidism. A critical unmet need exists for disease-modifying therapies that target its underlying pathogenesis. This study aimed to identify and validate novel therapeutic targets for AIT.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed an integrative genomics approach, combining genome-wide association studies (GWAS) with molecular quantitative trait loci (QTL) analyses, including expression (eQTL), protein (pQTL), and DNA methylation QTL (mQTL), across two independent AIT cohorts for discovery and replication. We performed two-sample bidirectional Mendelian randomization (MR) with sensitivity analyses, followed by summary-data-based MR (SMR) and heterogeneity in dependent instruments (HEIDI) tests. Top candidates were further evaluated via phenome-wide association study (PheWAS) and computational drug screening. Guided by these findings, we quantified plasma levels of the top-priority candidate, Ribonuclease T2 (RNASET2), via ELISA in AIT patients and non-AIT controls. To functionally validate its therapeutic potential, we developed a novel three-dimension (3D) inflammatory thyrocyte spheroid model and evaluated potential therapeutic effects of recombinant RNASET2. Loss-of-function (small interfering RNA-mediated knockdown) and gain-of-function (recombinant protein RNASET2 rescue) experiments further supported RNASET2 as a therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Multi-omics integration consistently nominated RNASET2 as a causal protective factor against AIT. Signals of pQTL and eQTL for RNASET2 were associated with decreased AIT risk, while three mQTLs were correlated with increased risk. PheWAS indicated minimal pleiotropic effects, supporting its therapeutic suitability. Computational drug screening nominated genistein, a soy isoflavone known to upregulate RNASET2 expression, as a repurposing candidate. Empirically, plasma RNASET2 levels were moderately elevated in AIT patients, potentially reflecting a compensatory anti-inflammatory response. Crucially, recombinant RNASET2 effectively mitigated inflammation and apoptosis in the thyrocyte spheroid model, confirming its functional protective role. Consistently, RNASET2 knockdown heightened susceptibility to inflammatory cell death and cytokine expression, a phenotype reversed by recombinant RNASET2 supplementation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>By integrating large-scale genomic analyses with functional validation, our study establishes RNASET2 as a promising therapeutic target for AIT. RNASET2 augmentation represents a potential disease-modifying strategy, providing a translational bridge from genetic discovery to clinical application.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1715937","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T05:15:55Z","timestamp":1770009355000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrative multi-omics Mendelian randomization and functional validation identifies RNASET2 as a novel therapeutic target for autoimmune thyroiditis"],"prefix":"10.3389","volume":"17","author":[{"given":"Bo","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of General Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University","place":["Nanjing, China"]},{"name":"Department of Thyroid Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxian","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University","place":["Nanjing, China"]},{"name":"Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqian","family":"Luo","sequence":"additional","affiliation":[{"name":"Clinical Medicine Research Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-020-01477-1","article-title":"An update on the pathogenesis of Hashimoto\u2019s thyroiditis","volume":"44","author":"Weetman","year":"2021","journal-title":"J Endocrinol Invest"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2022.100190","article-title":"A practical guideline of genomics-driven drug discovery in the era of global biobank meta-analysis","volume":"2","author":"Namba","year":"2022","journal-title":"Cell Genom"},{"key":"B3","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s10194-024-01828-w","article-title":"Multi-omics Mendelian randomization integrating GWAS, eQTL and pQTL data revealed GSTM4 as a potential drug target for migraine","volume":"25","author":"Sun","year":"2024","journal-title":"J Headache Pain"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.990486","article-title":"From classical mendelian randomization to causal networks for systematic integration of multi-omics","volume":"13","author":"Yazdani","year":"2022","journal-title":"Front Genet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e16","DOI":"10.1017\/pcm.2023.5","article-title":"Mendelian randomization as a tool to inform drug development using human genetics","volume":"1","author":"Daghlas","year":"2023","journal-title":"Camb Prism Precis Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e0316481","DOI":"10.1371\/journal.pone.0316481","article-title":"Exploring potential drug targets for SLE through Mendelian randomization and network pharmacology","volume":"20","author":"Xu","year":"2025","journal-title":"PloS One"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-024-07059-3","article-title":"Prioritizing drug targets in systemic lupus erythematosus from a genetic perspective: a druggable genome-wide Mendelian randomization study","volume":"43","author":"Gao","year":"2024","journal-title":"Clin Rheumatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1080\/08916934.2024.2330392","article-title":"Innovate therapeutic targets for autoimmune diseases: insights from proteome-wide mendelian randomization and Bayesian colocalization","volume":"57","author":"Jin","year":"2024","journal-title":"Autoimmunity"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104488","article-title":"Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases","volume":"89","author":"Yuan","year":"2023","journal-title":"EBioMedicine"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25052512","article-title":"Advantages of using 3D spheroid culture systems in toxicological and pharmacological assessment for osteogenesis research","volume":"25","author":"Yun","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00931-x","article-title":"A cross-population atlas of genetic associations for 220 human phenotypes","volume":"53","author":"Sakaue","year":"2021","journal-title":"Nat Genet"},{"key":"B12","doi-asserted-by":"publisher","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":"Vosa","year":"2021","journal-title":"Nat Genet"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06592-6","article-title":"Plasma proteomic associations with genetics and health in the UK Biobank","volume":"622","author":"Sun","year":"2023","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","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":"B15","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aag1166","article-title":"The druggable genome and support for target identification and validation in drug development","volume":"9","author":"Finan","year":"2017","journal-title":"Sci Transl Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Auton","year":"2015","journal-title":"Nature"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyr036","article-title":"Avoiding bias from weak instruments in Mendelian randomization studies","volume":"40","author":"Burgess","year":"2011","journal-title":"Int J Epidemiol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.18632\/aging.205867","article-title":"Leveraging pQTL-based Mendelian randomization to identify new treatment prospects for primary biliary cholangitis and primary sclerosing cholangitis","volume":"16","author":"Dai","year":"2024","journal-title":"Aging (Albany NY)"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1177\/0962280215597579","article-title":"A review of instrumental variable estimators for Mendelian randomization","volume":"26","author":"Burgess","year":"2017","journal-title":"Stat Methods Med Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-017-0255-x","article-title":"Interpreting findings from Mendelian randomization using the MR-Egger method","volume":"32","author":"Burgess","year":"2017","journal-title":"Eur J Epidemiol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet Epidemiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int J Epidemiol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.jclinepi.2014.09.005","article-title":"Cochran\u2019s Q test was useful to assess heterogeneity in likelihood ratios in studies of diagnostic accuracy","volume":"68","author":"Cohen","year":"2015","journal-title":"J Clin Epidemiol"},{"key":"B24","doi-asserted-by":"publisher","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":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3538","article-title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat Genet"},{"key":"B26","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1038\/s41467-018-03371-0","article-title":"Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits","volume":"9","author":"Wu","year":"2018","journal-title":"Nat Commun"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03855-y","article-title":"Rare variant contribution to human disease in 281,104 UK Biobank exomes","volume":"597","author":"Wang","year":"2021","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA methylation and its basic function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e36103","article-title":"Bioactive components in prunella vulgaris for treating Hashimoto\u2019s disease via regulation of innate immune response in human thyrocytes","volume":"10","author":"Chen","year":"2024","journal-title":"Heliyon"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2010.02425.x","article-title":"Differentiation imbalance of Th1\/Th17 in peripheral blood mononuclear cells might contribute to pathogenesis of Hashimoto\u2019s thyroiditis","volume":"72","author":"Shi","year":"2010","journal-title":"Scand J Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1098243","article-title":"The role behind the scenes of Tregs and Th17s in Hashimoto\u2019s thyroiditis: Toward a pivotal role of FOXP3 and BACH2","volume":"13","author":"Mazzieri","year":"2022","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"679","DOI":"10.3892\/etm.2022.11615","article-title":"TIM4\/NLRP3 axis participates in the effects of M1 macrophages on inflammatory factor release, apoptosis and cell adhesion in thyroid follicular cells","volume":"24","author":"Cao","year":"2022","journal-title":"Exp Ther Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.2174\/138920211798120763","article-title":"Hashimoto\u2019s thyroiditis: from genes to the disease","volume":"12","author":"Zaletel","year":"2011","journal-title":"Curr Genomics"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2011.0480","article-title":"Demonstration of innate immune responses in the thyroid gland: potential to sense danger and a possible trigger for autoimmune reactions","volume":"23","author":"Kawashima","year":"2013","journal-title":"Thyroid"},{"key":"B35","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.abb.2006.02.022","article-title":"Characterization of RNASET2, the first human member of the Rh\/T2\/S family of glycoproteins","volume":"449","author":"Campomenosi","year":"2006","journal-title":"Arch Biochem Biophys"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01554","article-title":"RNase T2 in inflammation and cancer: immunological and biological views","volume":"11","author":"Wu","year":"2020","journal-title":"Front Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2018.09.005","article-title":"The human RNASET2 protein affects the polarization pattern of human macrophages in vitro","volume":"203","author":"Scaldaferri","year":"2018","journal-title":"Immunol Lett"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12030717","article-title":"Overexpression of murine rnaset2 in a colon syngeneic mouse carcinoma model leads to rebalance of intra-tumor M1\/M2 macrophage ratio, activation of T cells, delayed tumor growth, and rejection","volume":"12","author":"De Vito","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B39","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.immuni.2020.03.009","article-title":"Immune sensing of synthetic, bacterial, and protozoan RNA by toll-like receptor 8 requires coordinated processing by RNase T2 and RNase 2","volume":"52","author":"Ostendorf","year":"2020","journal-title":"Immunity"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20241424","article-title":"RNase T2 restricts TLR13-mediated autoinflammation in vivo","volume":"222","author":"Gomez-Diaz","year":"2025","journal-title":"J Exp Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/ng.603","article-title":"Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC","volume":"42","author":"Quan","year":"2010","journal-title":"Nat Genet"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e0167212","DOI":"10.1371\/journal.pone.0167212","article-title":"Gene-based genome-wide association analysis in european and asian populations identified novel genes for rheumatoid arthritis","volume":"11","author":"Zhu","year":"2016","journal-title":"PloS One"},{"key":"B43","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1038\/ng.898","article-title":"A genome-wide association study identifies two new risk loci for Graves\u2019 disease","volume":"43","author":"Chu","year":"2011","journal-title":"Nat Genet"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nature11582","article-title":"Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease","volume":"491","author":"Jostins","year":"2012","journal-title":"Nature"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.04.002","article-title":"Association of ribonuclease T2 gene polymorphisms with decreased expression and clinical characteristics of severity in crohn\u2019s disease","volume":"153","author":"Gonsky","year":"2017","journal-title":"Gastroenterology"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.999155","article-title":"Diagnostic and therapeutic potential of RNASET2 in Crohn\u2019s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion","volume":"13","author":"Biener-Ramanujan","year":"2022","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00370","article-title":"Antimicrobial role of RNASET2 protein during innate immune response in the medicinal leech hirudo verbana","volume":"11","author":"Baranzini","year":"2020","journal-title":"Front Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxrep.2018.10.012","article-title":"Soy supplementation: Impact on gene expression in different tissues of ovariectomized rats and evaluation of the rat model to predict (post)menopausal health effect","volume":"5","author":"Islam","year":"2018","journal-title":"Toxicol Rep"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1715937\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T05:15:56Z","timestamp":1770009356000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1715937\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,2]]},"references-count":48,"alternative-id":["10.3389\/fendo.2026.1715937"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1715937","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,2]]},"article-number":"1715937"}}