{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:40:34Z","timestamp":1792172434779,"version":"4.4.0"},"reference-count":57,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2024JJ5601"],"award-info":[{"award-number":["2024JJ5601"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Tyrosine kinase 2 (TYK2)\u2010dependent cytokine signalling is integral to the pathogenesis of psoriasis. While BMS\u2010986165, a highly selective TYK2 inhibitor, has recently been approved for oral treatment of psoriasis, its therapeutic potential via topical application remains unexplored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>We aim to investigate the efficacy of topically applying TYK2 inhibitor in psoriasis and to elucidate the underlying mechanisms driving the therapeutic effects of this delivery approach.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>1.5% BMS\u2010986165 ointment was applied topically to the back skin of imiquimod (IMQ)\u2010induced psoriatic mice. To identify potential target cells influenced by the topical TYK2 inhibitor, we performed single cell RNA sequencing (scRNA\u2010seq) and flow cytometry on mouse lesions. The role of TYK2 in vitro was assessed by silencing its expression or administering BMS\u2010986165 in human keratinocytes (KCs). Mechanistic insights into TYK2 function in KCs were further investigated using RNA\u2010seq, dual luciferase reporter assay and ChIP\u2010qPCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>External use of 1.5% BMS\u2010986165 ointment significantly ameliorated the IMQ\u2010induced psoriasis\u2010like dermatitis. Importantly, topical TYK2 inhibitor attenuated proinflammatory capability of KCs. In vitro, TYK2 inhibition suppressed the transcription of nerve growth factor receptor (NGFR) by disrupting the AKT\u2010SP1 signalling pathway. This impairment hindered the activation of activator protein 1 (AP1), thereby weakening the proinflammatory potential of KCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study reveals a novel therapeutic potential for selective TYK2 inhibitor in topical manner on psoriasis therapy, which might prompt the development of topical treatment for psoriasis. Crucially, our findings provide an underexplored regulatory mechanism of TYK2 inhibitor in psoriasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Topical TYK2 inhibitor alleviates psoriasis\u2010like dermatitis.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Topical TYK2 inhibitor reduces psoriasis progression through restraining the inflammatory responses of keratinocytes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The inhibition of TYK2 regulates the inflammatory response of keratinocytes through AKT\u2010SP1\u2010NGFR\u2010AP1 pathway.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70256","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T08:49:47Z","timestamp":1741769387000},"source":"Crossref","is-referenced-by-count":7,"title":["Topical TYK2 inhibitor ameliorates psoriasis\u2010like dermatitis via the AKT\u2010SP1\u2010NGFR\u2010AP1 pathway in keratinocytes"],"prefix":"10.1002","volume":"15","author":[{"given":"Zhiqin","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital Central South University  Changsha Hunan China"},{"name":"National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rundong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital Central South University  Changsha Hunan China"},{"name":"National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology Central South University  Changsha Hunan China"},{"name":"Department of Dermatology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital Central South University  Changsha Hunan China"},{"name":"Clinical Medicine Eight\u2010Year Program, Xiangya School of Medicine Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangqing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital Central South University  Changsha Hunan China"},{"name":"National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital Central South University  Changsha Hunan China"},{"name":"National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6964-7131","authenticated-orcid":false,"given":"Mingzhu","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital Central South University  Changsha Hunan China"},{"name":"National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology Central South University  Changsha Hunan China"},{"name":"Clinical Research Center, Medical Pathology Center, Cancer Early Detection and Treatment Center, Chongqing University Three Gorges Hospital Chongqing University  Wanzhou Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.4006"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.82"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2014.11.012"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(20)32549\u20106"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(07)61128\u20103"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265\u2010020\u201001261\u20108"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(21)00184\u20107"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.03.014"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm401490p"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3646"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2016.07.038"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272\u2010020\u201001282\u20107"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaw1736"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1153"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05505"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00281\u2010019\u201000742\u20107"},{"key":"e_1_2_10_18_1","first-page":"S62","article-title":"Combined topical calcipotriene ointment 0.005% and various systemic therapies in the treatment of plaque\u2010type psoriasis vulgaris: review of the literature and results of a survey sent to 100 dermatologists","volume":"37","author":"Katz HI","year":"1997","journal-title":"J Am Acad Dermatol"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2013.06.027"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425247.2010.503953"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001655\u20106"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106642"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.03.069"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.12.007"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110787"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03963"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2123451119"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202012409"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1080\/09205063.2022.2068946"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010023\u201006134\u2010y"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1173"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2021.100141"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2021.06.019"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.12266"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00444"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2021.11.001"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600\u2010065X.2012.01152.x"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.2RU1116\u2010474R"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abn2263"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201039020\u20104"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201035565\u2010y"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.05.015"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061308"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939687"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032414-112123"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.818630"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113010"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.Can\u201010\u20102627"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2016.109"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.534206"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.688066"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12895\u2010016\u20100051\u20104"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104840"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2011.12.018"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(14)61909\u20107"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14871"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.70256","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T10:03:11Z","timestamp":1747735391000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.70256"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3]]},"references-count":57,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1002\/ctm2.70256"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.70256","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3]]},"article-number":"e70256"}}