{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T06:33:44Z","timestamp":1793169224098,"version":"4.5.0"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"20","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271614 81871097 81571371"],"award-info":[{"award-number":["82271614 81871097 81571371"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013088","name":"Qinglan Project of Jiangsu Province of China","doi-asserted-by":"publisher","award":["2024-14 and 2020-10 to J.J."],"award-info":[{"award-number":["2024-14 and 2020-10 to J.J."]}],"id":[{"id":"10.13039\/501100013088","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"JST | Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20151554"],"award-info":[{"award-number":["BK20151554"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jiangsu Province Ordinary University Innovative Research Project","award":["KYCX23_1916"],"award-info":[{"award-number":["KYCX23_1916"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,5,20]]},"abstract":"<jats:p>\n                    New immunosenescence targets for preventing senescence-associated pathological cardiac hypertrophy (SA-PCH) need to be explored. In the present study, with physiologically aged human and mouse samples, the IL-17A level increased with physiological aging, heart failure (HF), and SA-PCH and was negatively correlated with thymic Bmi-1 expression.\n                    <jats:italic toggle=\"yes\">\n                      Bmi-1\n                      <jats:sup>f\/f<\/jats:sup>\n                      LckCre\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    mice and\n                    <jats:italic toggle=\"yes\">\n                      Bmi-1\n                      <jats:sup>f\/f<\/jats:sup>\n                    <\/jats:italic>\n                    littermates were generated to determine whether Bmi-1 delayed T cell aging by maintaining thymic T cell development to prevent SA-PCH. As a result, Bmi-1 promoted thymic T cell development by upregulating Notch signaling and prevented DN1 T cells from differentiating into \u03b3\u03b4T17 cells by downregulating \u03b3\u03b4T17 cell differentiation signaling. Bmi-1 upregulated Notch signaling by inhibiting p53-mediated\n                    <jats:italic toggle=\"yes\">Ikzf1<\/jats:italic>\n                    transcription at the \u22121,863 to \u22121,849\n                    <jats:italic toggle=\"yes\">Ikzf1<\/jats:italic>\n                    promoter region. Bmi-1\u2013RING1B promoted ROR\u03b3t ubiquitination and degradation by proteasome to inhibit the production of IL-17A in \u03b3\u03b4T17 cells. Bmi-1 also downregulated\n                    <jats:italic toggle=\"yes\">Rorc<\/jats:italic>\n                    transcribed by c-Maf by trimethylating H3K27 at the \u22121,511 to \u22121,497\n                    <jats:italic toggle=\"yes\">Rorc<\/jats:italic>\n                    promoter region. Subsequently, the number of peripheral \u03b3\u03b4T17 cells infiltrating the heart tissues was reduced, while alleviating IL-17A-dependent cardiac aging, hypertrophy, dysfunction, senescence-associated secretory phenotype (SASP), and macrophage\u2013myofibroblast transition, ultimately improving SA-PCH. The ROR\u03b3t inhibitor SR1001 and IL-17A neutralizing antibody ixekizumab prevented thymic ROR\u03b3t-IL-17A-dependent SA-PCH. Furthermore, ROR\u03b3t bound to Bmi-1 through ARG237 and to RING1B through GLU235, which could be used as a therapeutic strategy for SA-PCH to construct binding peptides promoting Bmi-1\u2013RING1B binding to ROR\u03b3t and degrading ROR\u03b3t for inhibiting \u03b3\u03b4T17 cell differentiation and IL-17A production. Thus, thymic Bmi-1 prevented IL-17A-dependent SA-PCH by decreasing \u03b3\u03b4T17 cell numbers.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2414717122","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T11:28:01Z","timestamp":1747222081000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["Thymic Bmi-1 hampers \u03b3\u03b4T17 generation and its derived ROR\u03b3t-IL-17A signaling to delay cardiac aging"],"prefix":"10.1073","volume":"122","author":[{"given":"Qiuyi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8626-1695","authenticated-orcid":false,"given":"Haiyun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin\u2019ge","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingming","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Drum Tower Hospital, Medical School of Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mufeng","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Science and Technology, Jiangsu Health Vocational College","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3312-3210","authenticated-orcid":false,"given":"Jianliang","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.028728"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.574"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03547-7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.17219\/acem\/58802"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1621047114"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2015.04.001"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2019.04.005"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08040"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.884569"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.05.004"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1620"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.3.1236"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2019104159"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021110023"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2203318119"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-00986-z"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2021.09.005"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes13091643"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00746-9"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-023-00431-z"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13555-022-00743-9"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2020.1803063"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0673-2"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12918"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00715-08"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-00927-z"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1461919"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/wrr.12946"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301453"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2023.0320"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.12.013"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00348"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.05.057"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.10.019"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1663"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24203654"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202404518"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.10.863"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-014-1176-8"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2011.10.010"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.110.155895"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfy381"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13642"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2021.1970534"},{"key":"e_1_3_4_45_2","unstructured":"Y. Lin Data from \u201cLow-abundance mRNA-sequencing of DN1 phase T cells from 6-month-old thymic Bmi-1 conditional knockout mice and control littermates.\u201d Sequence Read Archive. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1019828. Deposited 22 September 2023."},{"key":"e_1_3_4_46_2","unstructured":"Y. Lin Data from \u201cmRNA transcriptome sequencing of heart tissues from 5-month-old wildtype mice 21-month-old wildtype mice and 21-month-old wildtype mice treated with Ixekizumab.\u201d Sequence Read Archive. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1028321. Deposited 16 October 2023."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2414717122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T11:28:57Z","timestamp":1747222137000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2414717122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,14]]},"references-count":46,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2025,5,20]]}},"alternative-id":["10.1073\/pnas.2414717122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2414717122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,14]]},"assertion":[{"value":"2024-07-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2414717122"}}