{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:11:00Z","timestamp":1790820660256,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea","award":["2019R1A2C3002751"],"award-info":[{"award-number":["2019R1A2C3002751"]}]},{"name":"National Research Foundation of Korea","award":["2020M3E5E2040018"],"award-info":[{"award-number":["2020M3E5E2040018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The number of people suffering from hair loss is increasing, and hair loss occurs not only in older men but also in women and young people. Prostaglandin D2 (PGD2) is a well-known alopecia inducer. However, the mechanism by which PGD2 induces alopecia is poorly understood. In this study, we characterized CXXC5, a negative regulator of the Wnt\/\u03b2-catenin pathway, as a mediator for hair loss by PGD2. The hair loss by PGD2 was restored by Cxxc5 knock-out or treatment of protein transduction domain\u2013Dishevelled binding motif (PTD-DBM), a peptide activating the Wnt\/\u03b2-catenin pathway via interference with the Dishevelled (Dvl) binding function of CXXC5. In addition, suppression of neogenic hair growth by PGD2 was also overcome by PTD-DBM treatment or Cxxc5 knock-out as shown by the wound-induced hair neogenesis (WIHN) model. Moreover, we found that CXXC5 also mediates DHT-induced hair loss via PGD2. DHT-induced hair loss was alleviated by inhibition of both GSK-3\u03b2 and CXXC5 functions. Overall, CXXC5 mediates the hair loss by the DHT-PGD2 axis through suppression of Wnt\/\u03b2-catenin signaling.<\/jats:p>","DOI":"10.3390\/cells12040555","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T02:32:07Z","timestamp":1675909927000},"page":"555","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["CXXC5 Mediates DHT-Induced Androgenetic Alopecia via PGD2"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9270-5408","authenticated-orcid":false,"given":"Yeong Chan","family":"Ryu","sequence":"first","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyeon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You-Rin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sehee","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2983-3252","authenticated-orcid":false,"given":"Geon-Uk","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunhwan","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumi","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heejene","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyoonhee","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soung-Hoon","family":"Lee","sequence":"additional","affiliation":[{"name":"CK Regeon Inc., B137 Engineering Research Park, 50 Yonsei Ro, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0952-3276","authenticated-orcid":false,"given":"Kang-Yell","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"},{"name":"CK Regeon Inc., B137 Engineering Research Park, 50 Yonsei Ro, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R132","DOI":"10.1016\/j.cub.2008.12.005","article-title":"The hair follicle as a dynamic miniorgan","volume":"19","author":"Schneider","year":"2009","journal-title":"Curr. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/JID.2015.354","article-title":"A Guide to Studying Human Hair Follicle Cycling In Vivo","volume":"136","author":"Oh","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s00403-018-1826-8","article-title":"Androgen modulation of Wnt\/\u03b2-catenin signaling in androgenetic alopecia","volume":"310","author":"Premanand","year":"2018","journal-title":"Arch. Dermatol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1080\/14728222.2019.1659779","article-title":"Androgenetic alopecia: Combing the hair follicle signaling pathways for new therapeutic targets and more effective treatment options","volume":"23","author":"Vasserot","year":"2019","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"126ra134","DOI":"10.1126\/scitranslmed.3003122","article-title":"Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia","volume":"4","author":"Garza","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/jid.2012.398","article-title":"Prostaglandin D2 inhibits wound-induced hair follicle neogenesis through the receptor, Gpr44","volume":"133","author":"Nelson","year":"2013","journal-title":"J. Investig. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ydbio.2013.11.023","article-title":"Wnt\/\u03b2-catenin signaling in dermal condensates is required for hair follicle formation","volume":"385","author":"Tsai","year":"2014","journal-title":"Dev. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Choi, B.Y. (2020). Targeting Wnt\/\u03b2-Catenin Pathway for Developing Therapies for Hair Loss. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21144915"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/jid.2012.230","article-title":"Epithelial Wnt ligand secretion is required for adult hair follicle growth and regeneration","volume":"133","author":"Myung","year":"2013","journal-title":"J. Investig. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/S1534-5807(02)00167-3","article-title":"WNT signals are required for the initiation of hair follicle development","volume":"2","author":"Andl","year":"2002","journal-title":"Dev. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nature05766","article-title":"Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding","volume":"447","author":"Ito","year":"2007","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1016\/j.jid.2017.04.038","article-title":"Targeting of CXXC5 by a Competing Peptide Stimulates Hair Regrowth and Wound-Induced Hair Neogenesis","volume":"137","author":"Lee","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1096\/fj.13-236216","article-title":"CXXC5 is a transcriptional activator of Flk-1 and mediates bone morphogenic protein-induced endothelial cell differentiation and vessel formation","volume":"28","author":"Kim","year":"2014","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/cdd.2014.238","article-title":"CXXC5 is a negative-feedback regulator of the Wnt\/\u03b2-catenin pathway involved in osteoblast differentiation","volume":"22","author":"Kim","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1111\/j.1365-2133.2012.10856.x","article-title":"Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt\/\u03b2-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia","volume":"166","author":"Attorresi","year":"2012","journal-title":"Br. J. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1210\/jc.2008-1053","article-title":"Keratinocyte growth inhibition through the modification of Wnt signaling by androgen in balding dermal papilla cells","volume":"94","author":"Kitagawa","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/ijc.26414","article-title":"A gene signature identified using a mouse model of androgen receptor-dependent prostate cancer predicts biochemical relapse in human disease","volume":"131","author":"Thompson","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/aps.2014.18","article-title":"Androgen receptor: Structure, role in prostate cancer and drug discovery","volume":"36","author":"Tan","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1111\/bph.15438","article-title":"KY19382, a novel activator of Wnt\/\u03b2-catenin signalling, promotes hair regrowth and hair follicle neogenesis","volume":"178","author":"Ryu","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1084\/jem.20141601","article-title":"The Dishevelled-binding protein CXXC5 negatively regulates cutaneous wound healing","volume":"212","author":"Lee","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1046\/j.0022-202x.2001.01377.x","article-title":"A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages","volume":"117","author":"Handjiski","year":"2001","journal-title":"J. Investig. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1242\/jcs.02793","article-title":"The hair cycle","volume":"119","author":"Alonso","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3672","DOI":"10.1074\/jbc.M808119200","article-title":"CXXC5 is a novel BMP4-regulated modulator of Wnt signaling in neural stem cells","volume":"284","author":"Andersson","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.3390\/ijms15011647","article-title":"Signaling involved in hair follicle morphogenesis and development","volume":"15","author":"Rishikaysh","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"878","DOI":"10.3748\/wjg.v21.i3.878","article-title":"Hes1, an important gene for activation of hepatic stellate cells, is regulated by Notch1 and TGF-\u03b2\/BMP signaling","volume":"21","author":"Zhang","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8712","DOI":"10.1093\/nar\/gkr572","article-title":"ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif","volume":"39","author":"Morikawa","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_27","first-page":"342","article-title":"The development of mouse vibrissae in vivo and in vitro","volume":"86","author":"Davidson","year":"1952","journal-title":"J. Anat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1600-0846.2011.00508.x","article-title":"Characterization and quantification of wound-induced hair follicle neogenesis using in vivo confocal scanning laser microscopy","volume":"17","author":"Fan","year":"2011","journal-title":"Ski. Res. Technol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/nm.3181","article-title":"Fgf9 from dermal \u03b3\u03b4 T cells induces hair follicle neogenesis after wounding","volume":"19","author":"Gay","year":"2013","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1095\/biolreprod.103.022079","article-title":"Expression and regulation of lipocalin-type prostaglandin d synthase in rat testis and epididymis","volume":"70","author":"Zhu","year":"2004","journal-title":"Biol. Reprod."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lee, S.H., Yoon, J., Shin, S.H., Zahoor, M., Kim, H.J., Park, P.J., Park, W.S., Min do, S., Kim, H.Y., and Choi, K.Y. (2012). Valproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034152"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1046\/j.1523-1747.2003.12168.x","article-title":"Androgenetic alopecia in women","volume":"8","author":"Price","year":"2003","journal-title":"J. Investig. Dermatol. Symp. Proc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e64","DOI":"10.1097\/GOX.0000000000000005","article-title":"Cause of androgenic alopecia: Crux of the matter","volume":"1","author":"Ustuner","year":"2013","journal-title":"Plast. Reconstr. Surg. Glob. Open"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1016\/j.jid.2017.07.826","article-title":"The Negative Regulator CXXC5: Making WNT Look a Little Less Dishevelled","volume":"137","author":"Kim","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"130","DOI":"10.2174\/187221312800166859","article-title":"Minoxidil use in dermatology, side effects and recent patents","volume":"6","author":"Rossi","year":"2012","journal-title":"Recent Pat. Inflamm. Allergy Drug Discov."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/jocd.12225","article-title":"Topical application of the Wnt\/\u03b2-catenin activator methyl vanillate increases hair count and hair mass index in women with androgenetic alopecia","volume":"15","author":"Tosti","year":"2016","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13785","DOI":"10.1038\/s41598-018-32138-2","article-title":"Morroniside regulates hair growth and cycle transition via activation of the Wnt\/\u03b2-catenin signaling pathway","volume":"8","author":"Zhou","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.jdermsci.2013.05.007","article-title":"Valproic acid promotes human hair growth in in vitro culture model","volume":"72","author":"Jo","year":"2013","journal-title":"J. Dermatol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1111\/1346-8138.12422","article-title":"Topical valproic acid increases the hair count in male patients with androgenetic alopecia: A randomized, comparative, clinical feasibility study using phototrichogram analysis","volume":"41","author":"Jo","year":"2014","journal-title":"J. Dermatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/sj.jid.5700999","article-title":"Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes","volume":"128","author":"Kwack","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.mce.2016.10.018","article-title":"Androgens modify Wnt agonists\/antagonists expression balance in dermal papilla cells preventing hair follicle stem cell differentiation in androgenetic alopecia","volume":"439","author":"Ceruti","year":"2017","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1210\/en.2009-1474","article-title":"A mouse model of androgenetic alopecia","volume":"151","author":"Crabtree","year":"2010","journal-title":"Endocrinology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"111247","DOI":"10.1016\/j.biopha.2021.111247","article-title":"Dihydrotestosterone-induced hair regrowth inhibition by activating androgen receptor in C57BL6 mice simulates androgenetic alopecia","volume":"137","author":"Fu","year":"2021","journal-title":"Biomed. Pharmacother. = Biomed. Pharmacother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1046\/j.1469-7580.2003.00140.x","article-title":"Mouse models for human hair loss disorders","volume":"202","author":"Porter","year":"2003","journal-title":"J. Anat."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/s41419-018-0765-9","article-title":"Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function","volume":"9","author":"Singh","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_46","first-page":"327","article-title":"Hair loss and regeneration performed on animal models","volume":"89","author":"Orasan","year":"2016","journal-title":"Med. Pharm. Rep."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/4\/555\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:27:50Z","timestamp":1760120870000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/4\/555"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,9]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["cells12040555"],"URL":"https:\/\/doi.org\/10.3390\/cells12040555","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,9]]}}}