{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:55:21Z","timestamp":1788328521969,"version":"build-2803163510"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"20","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004731","name":"MOST | NSFC | NSFC-Zhejiang Joint Fund | \u6d59\u6c5f\u7701\u79d1\u5b66\u6280\u672f\u5385 | Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LQN25H160023"],"award-info":[{"award-number":["LQN25H160023"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82403160"],"award-info":[{"award-number":["82403160"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC3400400"],"award-info":[{"award-number":["2022YFC3400400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Zhejiang Provincial Natural Science Foundation of China","award":["LZ25H160001"],"award-info":[{"award-number":["LZ25H160001"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,19]]},"abstract":"<jats:p>\n                    Intrahepatic cholangiocarcinoma (ICC) poses a significant clinical challenge due to its insidious onset, aggressive biological behavior, and propensity for early metastasis, contributing to a dismal 5-y survival rate of less than 10%. Despite advances in understanding the dynamic changes in gene regulatory networks and chromatin landscapes during tumorigenesis, the functional interplay between RNA epitranscriptomic modifications and nuclear events in ICC remains poorly elucidated. Here, we identify\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -acetyltransferase 10 (NAT10), the writer for\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    <jats:sup>4<\/jats:sup>\n                    -acetylcytidine (ac\n                    <jats:sup>4<\/jats:sup>\n                    C) mRNA modification, as a critical regulator of ICC malignancy. Integrated multiomics profiling reveals that NAT10-mediated ac\n                    <jats:sup>4<\/jats:sup>\n                    C modification enhances the mRNA stability of chromatin assembly factor 1 subunit A (CHAF1A), a key chromatin regulator. Mechanistically, the NAT10\u2013ac\n                    <jats:sup>4<\/jats:sup>\n                    C\u2013CHAF1A axis robustly and epigenetically suppresses the expression of the nuclear transposable element HERV9NC, leading to diminished double-stranded RNA accumulation. This epigenetic silencing not only fuels ICC proliferation and migration but also attenuates intrinsic innate immune responses, thereby fostering an immunosuppressive tumor microenvironment characterized by reduced cytotoxic T cell infiltration and impaired tumor surveillance. Pharmacological inhibition of NAT10 with small-molecule compounds demonstrated robust therapeutic efficacy in both patient-derived xenograft and orthotopic tumor transplantation models of ICC. Collectively, our study unveils NAT10 as a master integrator of RNA epitranscriptomic reprogramming and nuclear chromatin dynamics in ICC, providing interesting mechanistic insights into the molecular basis of ICC progression. We also establish NAT10-ac\n                    <jats:sup>4<\/jats:sup>\n                    C modification as a druggable vulnerability, offering a promising therapeutic strategy for this aggressive malignancy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2532263123","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T18:10:33Z","timestamp":1778782233000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["NAT10\/ac\n                    <sup>4<\/sup>\n                    C drives intrahepatic cholangiocarcinoma by suppressing transposable elements via chromatin remodeling"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7605-1259","authenticated-orcid":false,"given":"Yunkun","family":"Lu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments","place":["Hangzhou, China"]},{"name":"Provincial Key Laboratory of Minimally Invasive Procedure and Precision Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang University Cancer Center","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0124-1379","authenticated-orcid":false,"given":"Kainan","family":"Lin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments","place":["Hangzhou, China"]},{"name":"Provincial Key Laboratory of Minimally Invasive Procedure and Precision Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang University Cancer Center","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments","place":["Hangzhou, China"]},{"name":"Provincial Key Laboratory of Minimally Invasive Procedure and Precision Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang University Cancer Center","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Huang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments","place":["Hangzhou, China"]},{"name":"Provincial Key Laboratory of Minimally Invasive Procedure and Precision Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang University Cancer Center","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianyu","family":"Lin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04kx2sy84","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Life Science, Fujian Agriculture and Forestry University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Dou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments","place":["Hangzhou, China"]},{"name":"Provincial Key Laboratory of Minimally Invasive Procedure and Precision Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang University Cancer Center","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajuan","family":"Jiao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Gastroenterology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"Institute of Immunology, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments","place":["Hangzhou, China"]},{"name":"Provincial Key Laboratory of Minimally Invasive Procedure and Precision Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang University Cancer Center","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0075-581X","authenticated-orcid":false,"given":"Peng","family":"Xiao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Gastroenterology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"Institute of Immunology, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0936-2599","authenticated-orcid":false,"given":"Hongjun","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments","place":["Hangzhou, China"]},{"name":"Provincial Key Laboratory of Minimally Invasive Procedure and Precision Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang University Cancer Center","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silin","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments","place":["Hangzhou, China"]},{"name":"Provincial Key Laboratory of Minimally Invasive Procedure and Precision Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang University Cancer Center","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangtao","family":"Xue","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments","place":["Hangzhou, China"]},{"name":"Provincial Key Laboratory of Minimally Invasive Procedure and Precision Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang University Cancer Center","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-0865","authenticated-orcid":false,"given":"Shunmin","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences","place":["Beijing, China"]},{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6507-6442","authenticated-orcid":false,"given":"Junjie","family":"Xu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00ka6rp58","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments","place":["Hangzhou, China"]},{"name":"Provincial Key Laboratory of Minimally Invasive Procedure and Precision Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang University Cancer Center","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00240-3"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2017.157"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-020-0310-z"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2022.10.004"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00774-x"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-0253-2"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-1307-8_26"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.045"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.10.030"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.05.016"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-006-9390-5"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2009.03.007"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201540505"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18091924"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.04.047"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S197733"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.05.017"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.12.006"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202303814"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2023.216144"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-013-0748-7"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-019-09954-3"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adp5163"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.322244"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adh9871"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202302705"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2418-2"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2116735119"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202005047"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2018.11.009"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-018-0093-4"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2215155120"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature23449"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.153511"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adl1584"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2774-y"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24370"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05400-x"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1252651"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12595"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-022-01500-4"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00450-x"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70026"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2022.01.015"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-22-2233"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-022-02551-7"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature23465"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2532263123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T18:10:58Z","timestamp":1778782258000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2532263123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,14]]},"references-count":47,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2026,5,19]]}},"alternative-id":["10.1073\/pnas.2532263123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2532263123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,14]]},"assertion":[{"value":"2025-11-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2532263123"}}