{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T04:27:03Z","timestamp":1770265623943,"version":"3.49.0"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003693","name":"Korea Institute of Science and Technology","doi-asserted-by":"publisher","award":["2E33531"],"award-info":[{"award-number":["2E33531"]}],"id":[{"id":"10.13039\/501100003693","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003693","name":"Korea Institute of Science and Technology","doi-asserted-by":"publisher","award":["26Z0031"],"award-info":[{"award-number":["26Z0031"]}],"id":[{"id":"10.13039\/501100003693","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Education (MOE) and the Gangwon State","award":["2025-RISE-10-001"],"award-info":[{"award-number":["2025-RISE-10-001"]}]},{"name":"Ministry of Education (MOE) and the Gangwon State","award":["2025-RISE-10-005"],"award-info":[{"award-number":["2025-RISE-10-005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dysregulated extracellular matrix (ECM) deposition and epithelial\u2013mesenchymal transition (EMT) in the trabecular meshwork (TM) contribute to glaucoma-associated fibrotic remodeling, and lysophosphatidic acid (LPA) potently induces these profibrotic responses in human trabecular meshwork (HTM) cells. We investigated whether an ethanolic extract of Diospyros kaki leaves (EEDK) attenuates LPA-induced fibrosis and explored the underlying mechanisms. HTM cells were stimulated with LPA and treated with ethanol-based EEDK extracts. Expression of ECM\/fibrosis-related genes (FN1, ACTA2, COL1A1, COL3A1, COL4A1, COL6A2, CCN2) and EMT markers (CDH2, VIM, SNAI1) was assessed, along with cell migration using a wound-healing assay. Upstream regulatory pathways were examined via transcription factor prediction, AP-1 reporter assays, and analyses of MAPK\/AP-1 signaling. Among the extracts tested, the 70% ethanol EEDK extract showed the strongest antifibrotic activity, significantly reducing LPA-induced ECM gene\/protein expression and inhibiting HTM cell migration in a dose-dependent manner, whereas the 90% ethanol extract showed minimal effects. LPA robustly activated MAPK-dependent AP-1 signaling, and either pharmacologic inhibition of MAPK pathways or treatment with 70% ethanol EEDK comparably suppressed AP-1 activity and decreased downstream ECM\/EMT gene expression. Thus, 70% ethanol EEDK mitigates LPA-induced TM fibrosis by inhibiting MAPK\/AP-1-mediated transcription, supporting its potential as an antifibrotic strategy for glaucoma.<\/jats:p>","DOI":"10.3390\/ijms27031544","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T14:55:11Z","timestamp":1770216911000},"page":"1544","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Uncovering a Glaucoma-Linked Lysophosphatidic Acid\u2013MAPK\/AP-1 Fibrosis Axis in Human Trabecular Meshwork Cells and Its Modulation by Diospyros kaki Leaf Extract"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5673-5036","authenticated-orcid":false,"given":"Youngsic","family":"Jeon","sequence":"first","affiliation":[{"name":"Center for Natural Product Efficacy Optimization, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung 25451, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyukjoon","family":"Kwon","sequence":"additional","affiliation":[{"name":"Center for Natural Product Efficacy Optimization, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung 25451, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7429-3656","authenticated-orcid":false,"given":"Hong Ryul","family":"Ahn","sequence":"additional","affiliation":[{"name":"Center for Natural Product Efficacy Optimization, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung 25451, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyuwon","family":"Huh","sequence":"additional","affiliation":[{"name":"R&D Center, NovMetaPharma Co., Ltd., Seoul 06050, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9449-4763","authenticated-orcid":false,"given":"Taejung","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Natural Product Efficacy Optimization, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung 25451, Republic of Korea"},{"name":"Natural Product Applied Science, KIST School, University of Science and Technology, Gangneung 25451, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1787-1577","authenticated-orcid":false,"given":"Young-Tae","family":"Park","sequence":"additional","affiliation":[{"name":"Center for Natural Product Efficacy Optimization, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung 25451, Republic of Korea"},{"name":"Natural Product Applied Science, KIST School, University of Science and Technology, Gangneung 25451, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun Bong","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Natural Sciences, Gangneung-Wonju National University, Gangneung 25457, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7273-7279","authenticated-orcid":false,"given":"Jin-hyoung","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Healthcare Management, Catholic Kwandong University, Gangneung 25601, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae-hyun","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Digital Healthcare, Catholic Kwandong University, Gangneung 25601, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1080-0581","authenticated-orcid":false,"given":"Young-Joo","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Natural Product Efficacy Optimization, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung 25451, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang Hoon","family":"Jung","sequence":"additional","affiliation":[{"name":"Center for Natural Product Efficacy Optimization, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung 25451, Republic of Korea"},{"name":"Natural Product Applied Science, KIST School, University of Science and Technology, Gangneung 25451, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref_1","first-page":"563","article-title":"Normal-tension glaucoma: Pathogenesis and genetics","volume":"17","author":"Trivli","year":"2019","journal-title":"Exp. 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