{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:57:51Z","timestamp":1787320671360,"version":"build-2736575974"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":28,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82203907"],"award-info":[{"award-number":["82203907"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82404127"],"award-info":[{"award-number":["82404127"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82404137"],"award-info":[{"award-number":["82404137"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82430101"],"award-info":[{"award-number":["82430101"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273510"],"award-info":[{"award-number":["82273510"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M732651"],"award-info":[{"award-number":["2023M732651"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Discov."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The skin barrier is crucial for protecting against environmental challenges, preventing water loss, and regulating immune responses. This study aims to investigate the roles and mechanisms of SERPINB7 in skin barrier maintenance. We found that SERPINB7 deficiency disrupts tight junctions of keratinocytes in vitro, and specific knockout of\n                    <jats:italic>Serpinb7<\/jats:italic>\n                    in keratinocytes impairs skin barrier function in vivo. SERPINB7 deficiency leads to reduced expression of O-GalNAc regulatory proteins and structural abnormalities in the Golgi apparatus, ultimately impairing protein O-GalNAc glycosylation. Legumain acts as a critical mediator in the maintenance of normal biological functions and O-GalNAc glycosylation regulated by SERPINB7. O-GalNAc inhibition exhibits biological effects analogous to those induced by SERPINB7 deficiency, leading to weakened tight junctions, reduced cell adhesion, and compromised skin barrier integrity in keratinocytes and mouse skin, respectively. Consequently, O-GalNAc deficiency exacerbates inflammatory skin diseases such as psoriasis and atopic dermatitis. Mechanistically, O-GalNAc deficiency primarily affects the glycosylation of calcium-related and cell adhesion-related proteins, disrupting calcium signaling and compromising cell adhesion, ultimately leading to skin barrier dysfunction. In summary, this study demonstrates that SERPINB7 maintains skin barrier through protein O-GalNAc glycosylation. These findings not only deepen our understanding of skin barrier biology but also provide new insights for developing therapeutic strategies for skin barrier-related diseases.\n                  <\/jats:p>","DOI":"10.1038\/s41420-025-02935-6","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T06:44:31Z","timestamp":1767077071000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["SERPINB7 maintains skin barrier by regulating protein O-GalNAc glycosylation"],"prefix":"10.1038","volume":"12","author":[{"given":"Rui","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1052-4484","authenticated-orcid":false,"given":"Chen","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangfeng","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0171-8355","authenticated-orcid":false,"given":"Xin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"2935_CR1","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1126\/science.abo0693","volume":"376","author":"TA Harris-Tryon","year":"2022","unstructured":"Harris-Tryon TA, Grice EA. Microbiota and maintenance of skin barrier function. Science. 2022;376:940\u201345.","journal-title":"Science"},{"key":"2935_CR2","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1111\/jdv.20463","volume":"39","author":"Z Dajnoki","year":"2024","unstructured":"Dajnoki Z, Kapitany A, Eyerich K, Eyerich S, Torocsik D, Szegedi A. Topographical variations in the skin barrier and their role in disease pathogenesis. J Eur Acad Dermatol Venereol. 2024;39:1228\u201338.","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"2935_CR3","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1038\/s41590-018-0256-2","volume":"19","author":"T Dainichi","year":"2018","unstructured":"Dainichi T, Kitoh A, Otsuka A, Nakajima S, Nomura T, Kaplan DH, et al. The epithelial immune microenvironment (EIME) in atopic dermatitis and psoriasis. Nat Immunol. 2018;19:1286\u201398.","journal-title":"Nat Immunol"},{"key":"2935_CR4","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/nrm3175","volume":"12","author":"CL Simpson","year":"2011","unstructured":"Simpson CL, Patel DM, Green KJ. Deconstructing the skin: cytoarchitectural determinants of epidermal morphogenesis. Nat Rev Mol Cell Biol. 2011;12:565\u201380.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2935_CR5","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1016\/j.jid.2024.06.1280","volume":"144","author":"J Simmons","year":"2024","unstructured":"Simmons J, Gallo RL. The central roles of keratinocytes in coordinating skin immunity. J Invest Dermatol. 2024;144:2377\u201398.","journal-title":"J Invest Dermatol"},{"key":"2935_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-05045-8","volume":"13","author":"H Zheng","year":"2022","unstructured":"Zheng H, Gu L, Zhao F, Zhang C, Wang Z, Zhou H, et al. SerpinB7 deficiency contributes to development of psoriasis via calcium-mediated keratinocyte differentiation dysfunction. Cell Death Dis. 2022;13:635.","journal-title":"Cell Death Dis"},{"key":"2935_CR7","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/j.jid.2024.05.025","volume":"145","author":"S Li","year":"2025","unstructured":"Li S, Wu Y, Bu D, Hu L, Liu Y, Liu J, et al. SERPINB7 deficiency increases legumain activity and impairs the epidermal barrier in nagashima-type palmoplantar keratoderma. J Invest Dermatol. 2025;145:359\u201369.e8.","journal-title":"J Invest Dermatol"},{"key":"2935_CR8","doi-asserted-by":"publisher","first-page":"265","DOI":"10.5021\/ad.2018.30.3.265","volume":"30","author":"SE Lee","year":"2018","unstructured":"Lee SE, Lee SH. Skin barrier and calcium. Ann Dermatol. 2018;30:265\u201375.","journal-title":"Ann Dermatol"},{"key":"2935_CR9","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.3390\/biom11081213","volume":"11","author":"C D\u2019Arcy","year":"2021","unstructured":"D\u2019Arcy C, Kiel C. Cell adhesion molecules in normal skin and melanoma. Biomolecules. 2021;11:1213.","journal-title":"Biomolecules"},{"key":"2935_CR10","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1093\/bjd\/ljae134","volume":"191","author":"Y Liu","year":"2024","unstructured":"Liu Y, Liu J, Chen Y, Mo R, Xiang R, Song Z, et al. Potential digenic inheritance of SERPINB7 and SERPINA12 variants in Chinese patients with Nagashima-type palmoplantar keratosis. Br J Dermatol. 2024;191:136\u201338.","journal-title":"Br J Dermatol"},{"key":"2935_CR11","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1111\/j.1365-2133.2009.09156.x","volume":"161","author":"T Cheng","year":"2009","unstructured":"Cheng T, Tjabringa GS, van Vlijmen-Willems IM, Hitomi K, van Erp PE, Schalkwijk J, et al. The cystatin M\/E-controlled pathway of skin barrier formation: expression of its key components in psoriasis and atopic dermatitis. Br J Dermatol. 2009;161:253\u201364.","journal-title":"Br J Dermatol"},{"key":"2935_CR12","doi-asserted-by":"publisher","first-page":"15983","DOI":"10.3390\/ijms232415983","volume":"23","author":"R Solberg","year":"2022","unstructured":"Solberg R, Lunde NN, Forbord KM, Okla M, Kassem M, Jafari A. The mammalian cysteine protease legumain in health and disease. Int J Mol Sci. 2022;23:15983.","journal-title":"Int J Mol Sci"},{"key":"2935_CR13","doi-asserted-by":"publisher","DOI":"10.3389\/ebm.2024.10121","volume":"249","author":"L Zhou","year":"2024","unstructured":"Zhou L, Wu J, Wei Z, Zheng Y. Legumain in cardiovascular diseases. Exp Biol Med. 2024;249:10121.","journal-title":"Exp Biol Med"},{"key":"2935_CR14","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1078\/0171-9335-00388","volume":"83","author":"PL Zeeuwen","year":"2004","unstructured":"Zeeuwen PL. Epidermal differentiation: the role of proteases and their inhibitors. Eur J Cell Biol. 2004;83:761\u201373.","journal-title":"Eur J Cell Biol"},{"key":"2935_CR15","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1016\/j.semcdb.2010.02.001","volume":"21","author":"LA Tabak","year":"2010","unstructured":"Tabak LA. The role of mucin-type O-glycans in eukaryotic development. Semin Cell Dev Biol. 2010;21:616\u201321.","journal-title":"Semin Cell Dev Biol"},{"key":"2935_CR16","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1038\/s41596-024-01051-6","volume":"20","author":"MR Gadi","year":"2025","unstructured":"Gadi MR, Han J, Shen T, Fan S, Xiao Z, Li L. Divergent synthesis of amino acid-linked O-GalNAc glycan core structures. Nat Protoc. 2025;20:480\u2013517.","journal-title":"Nat Protoc"},{"key":"2935_CR17","doi-asserted-by":"publisher","first-page":"3666","DOI":"10.3390\/cells11223666","volume":"11","author":"Y Zhang","year":"2022","unstructured":"Zhang Y, Sun L, Lei C, Li W, Han J, Zhang J, et al. A sweet warning: mucin-type O-glycans in cancer. Cells. 2022;11:3666.","journal-title":"Cells"},{"key":"2935_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33806-8","volume":"13","author":"MI Nielsen","year":"2022","unstructured":"Nielsen MI, de Haan N, Kightlinger W, Ye Z, Dabelsteen S, Li M, et al. Global mapping of GalNAc-T isoform-specificities and O-glycosylation site-occupancy in a tissue-forming human cell line. Nat Commun. 2022;13:6257.","journal-title":"Nat Commun"},{"key":"2935_CR19","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2023.2197833","volume":"15","author":"SA Raev","year":"2023","unstructured":"Raev SA, Amimo JO, Saif LJ, Vlasova AN. Intestinal mucin-type O-glycans: the major players in the host-bacteria-rotavirus interactions. Gut Microbes. 2023;15:2197833.","journal-title":"Gut Microbes"},{"key":"2935_CR20","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/978-3-030-70115-4_2","volume":"1325","author":"I Bagdonaite","year":"2021","unstructured":"Bagdonaite I, Pallesen EMH, Nielsen MI, Bennett EP, Wandall HH. Mucin-type O-GalNAc glycosylation in health and disease. Adv Exp Med Biol. 2021;1325:25\u201360.","journal-title":"Adv Exp Med Biol"},{"key":"2935_CR21","doi-asserted-by":"publisher","first-page":"5939","DOI":"10.2147\/JIR.S327609","volume":"14","author":"Y Zhang","year":"2021","unstructured":"Zhang Y, Wang L, Ocansey DKW, Wang B, Wang L, Xu Z. Mucin-type O-glycans: barrier, microbiota, and immune anchors in inflammatory bowel disease. J Inflamm Res. 2021;14:5939\u201353.","journal-title":"J Inflamm Res"},{"key":"2935_CR22","doi-asserted-by":"publisher","first-page":"7033","DOI":"10.3390\/molecules28207033","volume":"28","author":"L Sun","year":"2023","unstructured":"Sun L, Zhang Y, Li W, Zhang J, Zhang Y. Mucin glycans: a target for cancer therapy. Molecules. 2023;28:7033.","journal-title":"Molecules"},{"key":"2935_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46825-4","volume":"15","author":"L Bechtella","year":"2024","unstructured":"Bechtella L, Chunsheng J, Fentker K, Erturk GR, Safferthal M, Polewski L, et al. Ion mobility-tandem mass spectrometry of mucin-type O-glycans. Nat Commun. 2024;15:2611.","journal-title":"Nat Commun"},{"key":"2935_CR24","doi-asserted-by":"publisher","first-page":"14189","DOI":"10.1021\/ja405189k","volume":"135","author":"K Agarwal","year":"2013","unstructured":"Agarwal K, Kaul R, Garg M, Shajahan A, Jha SK, Sampathkumar SG. Inhibition of mucin-type O-glycosylation through metabolic processing and incorporation of N-thioglycolyl-D-galactosamine peracetate (Ac5GalNTGc). J Am Chem Soc. 2013;135:14189\u201397.","journal-title":"J Am Chem Soc"},{"key":"2935_CR25","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.bbrc.2018.08.131","volume":"506","author":"V Dwivedi","year":"2018","unstructured":"Dwivedi V, Saini P, Tasneem A, Agarwal K, Sampathkumar SG. Differential inhibition of mucin-type O-glycosylation (MTOG) induced by peracetyl N-thioglycolyl-d-galactosamine (Ac(5)GalNTGc) in myeloid cells. Biochem Biophys Res Commun. 2018;506:60\u201365.","journal-title":"Biochem Biophys Res Commun"},{"key":"2935_CR26","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/j.chembiol.2021.01.017","volume":"28","author":"SS Wang","year":"2021","unstructured":"Wang SS, Solar VD, Yu X, Antonopoulos A, Friedman AE, Agarwal K, et al. Efficient inhibition of O-glycan biosynthesis using the hexosamine analog Ac(5)GalNTGc. Cell Chem Biol. 2021;28:699\u2013710.e5.","journal-title":"Cell Chem Biol"},{"key":"2935_CR27","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/s41392-022-01219-0","volume":"8","author":"Q Zhao","year":"2023","unstructured":"Zhao Q, Yu J, Zhou H, Wang X, Zhang C, Hu J, et al. Intestinal dysbiosis exacerbates the pathogenesis of psoriasis-like phenotype through changes in fatty acid metabolism. Signal Transduct Target Ther. 2023;8:40.","journal-title":"Signal Transduct Target Ther"},{"key":"2935_CR28","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abp9159","volume":"14","author":"J Chavarria-Smith","year":"2022","unstructured":"Chavarria-Smith J, Chiu CPC, Jackman JK, Yin J, Zhang J, Hackney JA, et al. Dual antibody inhibition of KLK5 and KLK7 for Netherton syndrome and atopic dermatitis. Sci Transl Med. 2022;14:eabp9159.","journal-title":"Sci Transl Med"}],"container-title":["Cell Death Discovery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41420-025-02935-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-025-02935-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-025-02935-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T17:02:58Z","timestamp":1769533378000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41420-025-02935-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,30]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2935"],"URL":"https:\/\/doi.org\/10.1038\/s41420-025-02935-6","relation":{},"ISSN":["2058-7716"],"issn-type":[{"value":"2058-7716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,30]]},"assertion":[{"value":"27 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 December 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 December 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 December 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. Studies involving human samples were authorized by the Ethics Committee of Shanghai Skin Disease Hospital, with approval number 2024-38. All participants provided their written informed consent prior to participation. The animal study was approved by the Ethics Committee of the Shanghai Skin Disease Hospital (2024-72).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"66"}}