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We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline\u2010rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne\/\u201cmetabolizing acquired dioxin\u2010induced skin hamartomas\u201d (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2\u2010dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis.<\/jats:p>","DOI":"10.1002\/emmm.201303281","type":"journal-article","created":{"date-parts":[[2014,2,10]],"date-time":"2014-02-10T15:57:53Z","timestamp":1392047873000},"page":"442-457","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":98,"title":["Activation of Nrf2 in keratinocytes causes chloracne (MADISH)\u2010like skin disease in mice"],"prefix":"10.1038","volume":"6","author":[{"given":"Matthias","family":"Sch\u00e4fer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann\u2010Helen","family":"Willrodt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svitlana","family":"Kurinna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea S","family":"Link","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hany","family":"Farwanah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Geusau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Gruber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Sorg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron J","family":"Huebner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis R","family":"Roop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konrad","family":"Sandhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Hilaire","family":"Saurat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwin","family":"Tschachler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlon R","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutz","family":"Langbein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilhelm","family":"Bloch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans\u2010Dietmar","family":"Beer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Werner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,2,6]]},"reference":[{"key":"BFEMMM201303281_CR1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.brainres.2013.07.039","volume":"1531","author":"FA Brackmann","year":"2013","unstructured":"Brackmann FA, Link AS, Jung S, Richter M, Zoglauer D, Walkinshaw G, Alzheimer C, Trollmann R (2013) Activin A regulation under global hypoxia in developing mouse brain. 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J Cell Biol 188: 935\u2013952","journal-title":"J Cell Biol"}],"container-title":["EMBO Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1002\/emmm.201303281.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/emmm.201303281","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1002\/emmm.201303281\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.embopress.org\/doi\/pdf\/10.1002\/emmm.201303281","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1002\/emmm.201303281.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T06:08:24Z","timestamp":1779084504000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1002\/emmm.201303281"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,2,6]]},"references-count":41,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2014,4,1]]}},"alternative-id":["BFEMMM201303281"],"URL":"https:\/\/doi.org\/10.1002\/emmm.201303281","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.718269223.793522756","asserted-by":"object"}]},"ISSN":["1757-4676","1757-4684"],"issn-type":[{"value":"1757-4676","type":"print"},{"value":"1757-4684","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,2,6]]},"assertion":[{"value":"12 July 2013","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 January 2014","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 January 2014","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 February 2014","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Problem\n                      The Nrf2 transcription factor is a key regulator of genes involved in the antioxidant defense system. Therefore, it is an attractive pharmacological target for skin protection and cancer prevention. The consequences of long\u2010term Nrf2 activation in the skin, however, remain to be determined.\n                      Results\n                      Here we show that prolonged genetic and pharmacological activation of Nrf2 in mouse keratinocytes leads to sebaceous gland enlargement combined with hyperkeratosis and acanthosis of the hair follicle infundibula. Together, this caused dilatation of infundibula, hair loss, and development of large keratinized skin cysts upon aging.Sebaceous gland enlargement resulted from increased expression of the novel Nrf2 target epigen (Epgn), an epidermal growth factor (EGF) family member, which caused sebocyte proliferation. Moreover, upregulation of Epgn, secretory leukocyte peptidase inhibitor (Slpi), and small proline\u2010rich protein 2d (Sprr2d) are responsible for the hair follicle abnormalities and cyst formation upon aging.These alterations show remarkable similarities to the cutaneous abnormalities of patients with chloracne\/\u201cmetabolizing acquired dioxin\u2010induced skin hamartomas\u201d (MADISH), a severe pathology that develops upon dioxin poisoning. The functional relevance for MADISH pathogenesis was reflected by the strong expression of the NRF2 targets NQO1, SLPI, SPRR2D, and EPGN in affected skin of these patients and the dioxin\u2010mediated upregulation of these genes in human keratinocytes, which occurred in an NRF2\u2010dependent manner.\n                      Impact\n                      These results identified novel and unexpected activities of Nrf2 in the control of hair follicle and sebaceous gland homeostasis, which need to be considered when Nrf2\u2010activating compounds are used for skin protection and cancer prevention. Most importantly, they provide first evidence for a role of NRF2 and downstream targets in the pathogenesis of MADISH.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"The paper explained"}}]}}