{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T07:12:42Z","timestamp":1775805162316,"version":"3.50.1"},"reference-count":41,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"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":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The mechanisms by which the autosomal dominant disorder tuberous sclerosis complex (TSC) results in liver fibrosis remain poorly understood. KDM6A, a histone demethylase, has been implicated in the pathogenesis of fibrosis in multiple tissues. This study aimed to elucidate the molecular mechanism by which KDM6A contributed to TSC\u2010associated fibrosis. We observed fibrogenesis, epithelial\u2013mesenchymal transition (EMT) induction and upregulation of Kdm6a in\u00a0vivo and in\u00a0vitro upon\n                    <jats:italic>Tsc1<\/jats:italic>\n                    or\n                    <jats:italic>Tsc2<\/jats:italic>\n                    deficiency. Knockdown of\n                    <jats:italic>Kdm6a<\/jats:italic>\n                    attenuated both fibrosis and EMT phenotypes. Mechanistically,\n                    <jats:italic>Kdm6a<\/jats:italic>\n                    depletion reduced phosphorylation of ERK1\/2 and downregulated Snai1 expression. Activation of the MAPK\/ERK pathway with PMA restored EMT\u2010related protein expression, confirming the functional involvement of this signaling axis. Furthermore,\n                    <jats:italic>Tsc1<\/jats:italic>\n                    or\n                    <jats:italic>Tsc2<\/jats:italic>\n                    deficiency promoted Kdm6a expression via the mTORC1 pathway, while\n                    <jats:italic>Kdm6a<\/jats:italic>\n                    knockdown conversely suppressed mTORC1 activity by reducing mTOR protein expression, suggesting a positive feedback loop between Kdm6a expression and mTORC1. These findings indicate that Kdm6a promotes fibrosis in TSC through the activation of the MAPK\/ERK\/SNAI1 signaling pathway. Moreover, the combination of mTORC1 and KDM6A inhibitors results in marked regression of fibrosis and liver lesions in TSC models, unveiling a potential treatment for TSC patients with inadequate response to mTORC1 inhibitors.\n                  <\/jats:p>","DOI":"10.1111\/cge.70136","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T06:15:09Z","timestamp":1767852909000},"page":"912-925","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Collagen Deposition in Tuberous Sclerosis Complex Is Driven Through KDM6A\u2010Mediated Activation of ERK\/SNAI1 Signaling"],"prefix":"10.1111","volume":"109","author":[{"given":"Xin","family":"Lei","sequence":"first","affiliation":[{"name":"Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Institutes of Biomedical Sciences Shanxi University  Taiyuan China"},{"name":"Department of Reproductive Medicine Shanxi Provincial People's Hospital  Taiyuan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Lang","sequence":"additional","affiliation":[{"name":"Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Institutes of Biomedical Sciences Shanxi University  Taiyuan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shan","family":"Gao","sequence":"additional","affiliation":[{"name":"Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health Southeast University  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1511-9843","authenticated-orcid":false,"given":"Han","family":"Xiao","sequence":"additional","affiliation":[{"name":"Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Institutes of Biomedical Sciences Shanxi University  Taiyuan China"},{"name":"Next Level Genomics Pte Ltd  Singapore City Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7416-1662","authenticated-orcid":false,"given":"Changxin","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Institutes of Biomedical Sciences Shanxi University  Taiyuan China"},{"name":"Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China Shanxi University  Taiyuan China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2011.04.002"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10071587"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000101322"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10565-024-09858-5"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000106015.29070.E7"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3363"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/3853242"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389201024666230320100504"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-01449-y"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI138577"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1452"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI83239"},{"issue":"4","key":"e_1_2_11_14_1","first-page":"788","article-title":"Inhibition of KDM6 Activity During Murine ESC Differentiation Induces DNA Damage","volume":"129","author":"Hofstetter C.","year":"2016","journal-title":"Journal of Cell Science"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27107"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI95946"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23169407"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-016-0734-z"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/8814163"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1896"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/cup.14340"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.14392"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13102888"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2025.111418"},{"issue":"8","key":"e_1_2_11_25_1","first-page":"4946","article-title":"The Inhibition of SGK1 Suppresses Epithelial\u2010Mesenchymal Transition and Promotes Renal Tubular Epithelial Cell Autophagy in Diabetic Nephropathy","volume":"11","author":"Zhuang L.","year":"2019","journal-title":"American Journal of Translational Research"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090233"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2206"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP277367"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26012"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-015-1472-2"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1159\/000456281"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-14-0220"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu16070965"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.31083\/j.fbl2901006"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-49565-5"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(05)70168-6"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.4251\/wjgo.v17.i5.104686"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3758"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.4"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07818-3"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2025.07.001"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-325405"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70136","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70136","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70136","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:24:04Z","timestamp":1775802244000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,7]]},"references-count":41,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1111\/cge.70136"],"URL":"https:\/\/doi.org\/10.1111\/cge.70136","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,7]]},"assertion":[{"value":"2025-11-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}