{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:56:05Z","timestamp":1785426965942,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002641","name":"Konkuk University","doi-asserted-by":"publisher","award":["2023"],"award-info":[{"award-number":["2023"]}],"id":[{"id":"10.13039\/501100002641","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2023"],"award-info":[{"award-number":["2023"]}],"id":[{"id":"https:\/\/ror.org\/025h1m602","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dermal papilla (DP) cells orchestrate hair follicle growth and cycling by secreting signaling molecules that stimulate follicular epithelial stem cells. The signal peptide CUB-EGF-like domain-containing protein 3 (SCUBE3) was recently identified as a potent anagen stimulator secreted by DP cells. Ageratum houstonianum ethanolic extract (AHE) and its active constituent agerarin exhibit anti-inflammatory properties; however, their effects on hair follicle growth remain unclear. This study aimed to investigate the effects of AHE and agerarin on SCUBE3 expression in primary human DP cells and to elucidate the underlying molecular signaling pathway. Cell viability was assessed by measuring cell confluency. Ex vivo hair growth was analyzed using organ cultures of human hair follicles. Gene and protein expression were determined using reverse transcription-PCR, immunoblot analysis, immunofluorescent staining, tyramide signal amplification-based multiplex immunohistochemistry, and gene promoter-reporter assay in primary human follicle DP cells. In a hair follicle organ culture model, both AHE and agerarin increased the population of the anagen phase and promoted hair shaft elongation. AHE and agerarin significantly upregulated SCUBE3 expression at both the mRNA and protein levels. Mechanistically, AHE and agerarin induced activator protein-1 (AP-1) expression by activating mitogen-activated protein kinase signaling pathways, thereby increasing SCUBE3 gene promoter activity. AHE and agerarin promoted hair follicle growth by upregulating SCUBE3 expression via activation of the MAPK\u2013AP-1 signaling axis. In conclusion, AHE and agerarin may serve as potential therapeutic agents for the prevention and treatment of alopecia (hair loss).<\/jats:p>","DOI":"10.3390\/ijms27083679","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T07:57:21Z","timestamp":1776758241000},"page":"3679","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ageratum houstonianum Extract and Agerarin Promote Hair Growth via MAPK\/AP-1 Axis-Dependent Upregulation of SCUBE3 in Human Dermal Papilla Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Yongjin","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, College of Lifesciences, Konkuk University, Seoul 05029, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3091-0649","authenticated-orcid":false,"given":"Euitaek","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Lifesciences, Konkuk University, Seoul 05029, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4544-8530","authenticated-orcid":false,"given":"Gyungmin","family":"Cho","sequence":"additional","affiliation":[{"name":"Skin Science Lab, AgeraMedi, Inc., Seoul 05029, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yena","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Lifesciences, Konkuk University, Seoul 05029, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1075-0011","authenticated-orcid":false,"given":"Soon Young","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Lifesciences, Konkuk University, Seoul 05029, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13287-025-04210-y","article-title":"Functional regeneration strategies of hair follicles: Advances and challenges","volume":"16","author":"Chu","year":"2025","journal-title":"Stem Cell Res. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"a015180","DOI":"10.1101\/cshperspect.a015180","article-title":"The dermal papilla: An instructive niche for epithelial stem and progenitor cells in development and regeneration of the hair follicle","volume":"4","author":"Morgan","year":"2014","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"37485","DOI":"10.1074\/jbc.M405912200","article-title":"A Novel Secreted, Cell-surface Glycoprotein Containing Multiple Epidermal Growth Factor-like Repeats and One CUB Domain Is Highly Expressed in Primary Osteoblasts and Bones","volume":"279","author":"Wu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12929-023-00925-3","article-title":"The biology of SCUBE","volume":"30","author":"Lin","year":"2023","journal-title":"J. Biomed. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1016\/j.devcel.2022.06.005","article-title":"Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state","volume":"57","author":"Liu","year":"2022","journal-title":"Dev. Cell"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ilesanmi, A., Stevens-Washington, C., Jones, S., Alarcon, K., Aryal, A., Subbarayalu, P., Shackleford, T.J., Crossley, D., and Onyeagucha, B.C. (2026). Signal Peptide-CUB-EGF-like Domain-Containing Protein 3 (SCUBE3): From Molecule to Therapy. Therapeutics, 3.","DOI":"10.3390\/therapeutics3010005"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1159\/000542876","article-title":"Herbal Remedies for Hair Loss: A Review of Efficacy and Safety","volume":"11","author":"Ahmed","year":"2025","journal-title":"Ski. Appendage Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1055\/a-2494-9020","article-title":"Plants with hair growth activity for alopecia: A scoping review on methodological aspects","volume":"91","author":"Galende","year":"2025","journal-title":"Planta Medica"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11175","DOI":"10.1038\/s41598-017-11642-x","article-title":"Agerarin, identified from Ageratum houstonianum, stimulates circadian CLOCK-mediated aquaporin-3 gene expression in HaCaT keratinocytes","volume":"7","author":"Shin","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_10","first-page":"449","article-title":"Effect of 6, 7-dimethoxy-2, 2-dimethyl-2H-chromene (agerarin) on the recovery of filaggrin expression through targeting of Janus kinases in the inflammatory skin","volume":"28","author":"Ahn","year":"2020","journal-title":"J. Food Drug Anal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1128\/MMBR.00031-10","article-title":"Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases","volume":"75","author":"Cargnello","year":"2011","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1186\/s13287-025-04420-4","article-title":"Pathophysiological mechanisms of hair follicle regeneration and potential therapeutic strategies","volume":"16","author":"Bellani","year":"2025","journal-title":"Stem. Cell Res. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s001090050063","article-title":"Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways","volume":"74","author":"Whitmarsh","year":"1996","journal-title":"J. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s12192-020-01083-3","article-title":"Tanshinone IIA pretreatment promotes cell survival in human lung epithelial cells under hypoxia via AP-1-Nrf2 transcription factor","volume":"25","author":"Yadav","year":"2020","journal-title":"Cell Stress Chaperones"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16483","DOI":"10.1074\/jbc.270.28.16483","article-title":"The regulation of AP-1 activity by mitogen-activated protein kinases","volume":"270","author":"Karin","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s11033-019-05123-9","article-title":"Expression and function of FRA1 protein in tumors","volume":"47","author":"Jiang","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1038\/sj.onc.1204380","article-title":"Function and regulation of AP-1 subunits in skin physiology and pathology","volume":"20","author":"Angel","year":"2001","journal-title":"Oncogene"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhang, H.-L., Qiu, X.-X., and Liao, X.-H. (2024). Dermal papilla cells: From basic research to translational applications. Biology, 13.","DOI":"10.3390\/biology13100842"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1046\/j.0022-202X.2004.22224.x","article-title":"Wnt Signaling through the \u03b2-Catenin Pathway Is Sufficient to Maintain, but Not Restore, Anagen-Phase Characteristics of Dermal Papilla Cells","volume":"122","author":"Shimizu","year":"2004","journal-title":"J. Investig. Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1101\/gad.14.10.1181","article-title":"Wnt signaling maintains the hair-inducing activity of the dermal papilla","volume":"14","author":"Kishimoto","year":"2000","journal-title":"Genes Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3583","DOI":"10.1016\/j.jia.2023.10.012","article-title":"FGF7 secreted from dermal papillae cell regulates the proliferation and differentiation of hair follicle stem cell","volume":"24","author":"Wang","year":"2025","journal-title":"J. Integr. Agric."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/scd.2023.0156","article-title":"The role of mesenchymal stem cells in hair regeneration and hair cycle","volume":"33","author":"Ma","year":"2024","journal-title":"Stem Cells Dev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E131","DOI":"10.1038\/ncb0502-e131","article-title":"AP-1 as a regulator of cell life and death","volume":"4","author":"Shaulian","year":"2002","journal-title":"Nat. Cell Biol."},{"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":"2390","DOI":"10.1038\/sj.onc.1204383","article-title":"AP-1 in cell proliferation and survival","volume":"20","author":"Shaulian","year":"2001","journal-title":"Oncogene"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s40538-023-00499-0","article-title":"JUNB affects hair follicle development and regeneration by promoting the proliferation of dermal papilla cells in goat","volume":"10","author":"Zhang","year":"2023","journal-title":"Chem. Biol. Technol. Agric."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.bbapap.2009.11.002","article-title":"c-Jun N-terminal kinase (JNK) signaling: Recent advances and challenges","volume":"1804","author":"Bogoyevitch","year":"2010","journal-title":"Biochim. Biophys. Acta (BBA)-Proteins Proteom."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.stem.2013.10.003","article-title":"Distinct functions for Wnt\/\u03b2-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis","volume":"13","author":"Choi","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1111\/bjd.18356","article-title":"Deciphering the molecular morphology of the human hair cycle: Wnt signalling during the telogen\u2013anagen transformation","volume":"182","author":"Hawkshaw","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/cr.2008.302","article-title":"Signaling cross-talk between TGF-beta\/BMP and other pathways","volume":"19","author":"Guo","year":"2009","journal-title":"Cell Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"112127","DOI":"10.1016\/j.mce.2023.112127","article-title":"\u03b2-catenin\/TCF4-induced SCUBE3 upregulation promotes ovarian cancer development via HIF-1 signaling pathway","volume":"582","author":"Shen","year":"2024","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3759","DOI":"10.1111\/jocd.14537","article-title":"Treatment options for androgenetic alopecia: Efficacy, side effects, compliance, financial considerations, and ethics","volume":"20","author":"Nestor","year":"2021","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1111\/exd.12836","article-title":"Human hair follicle organ culture: Theory, application and perspectives","volume":"24","author":"Langan","year":"2015","journal-title":"Exp. Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1111\/j.1600-0625.2009.00939.x","article-title":"Methods in hair research: How to objectively distinguish between anagen and catagen in human hair follicle organ culture","volume":"19","author":"Kloepper","year":"2010","journal-title":"Exp. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Yeo, H., Lee, Y.H., Ahn, S.S., Jung, E., Lim, Y., and Shin, S.Y. (2021). Chrysin Inhibits TNF\u03b1-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094350"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3679\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:15:29Z","timestamp":1776917729000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,20]]},"references-count":35,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27083679"],"URL":"https:\/\/doi.org\/10.3390\/ijms27083679","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,20]]}}}