{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:37:59Z","timestamp":1793277479259,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T00:00:00Z","timestamp":1757030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Epithelial-mesenchymal transition (EMT) in the lung is a key process in which pulmonary epithelial cells lose epithelial characteristics and acquire mesenchymal properties, contributing to conditions such as pulmonary fibrosis. This study investigates the potential of pinostilbene (PIN), a natural stilbene compound with known anti-cancer, antioxidant and anti-inflammatory properties, to inhibit pulmonary EMT. Cellular experiments using A549 and Beas2B cells showed that PIN significantly reduced TGF-\u03b21-induced mesenchymal marker expression while increasing epithelial marker expression. Functional assays confirmed the ability of PIN to inhibit cell migration and adhesion. <jats:italic>In vivo<\/jats:italic>, PIN alone or in combination with pirfenidone effectively alleviated lung damage in a murine lung fibrosis model, as demonstrated by histological analysis. Mechanistic studies identified the PI3K\/Akt pathway as a target of PIN, with Western blot analysis showing decreased phosphorylation levels of PI3K and Akt. These findings suggest that PIN inhibits pulmonary EMT and delays the progression of pulmonary fibrosis by modulating the PI3K\/Akt pathway, providing a promising therapeutic avenue for lung diseases associated with EMT.<\/jats:p>","DOI":"10.3389\/fphar.2025.1614546","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T05:32:22Z","timestamp":1757050342000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Pinostilbene inhibits lung epithelial-mesenchymal transition and delays pulmonary fibrosis by modulating the PI3K\/Akt pathway"],"prefix":"10.3389","volume":"16","author":[{"given":"Xin","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianying","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefang","family":"Kou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhe","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengzhen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaihui","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixing","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanguo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.jnutbio.2017.10.015","article-title":"Resveratrol and pinostilbene confer neuroprotection against aging-related deficits through an ERK1\/2-dependent mechanism","volume":"54","author":"Allen","year":"2018","journal-title":"J. Nutr. Biochem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/s10555-023-10126-x","article-title":"Resveratrol as sensitizer in colorectal cancer plasticity","volume":"43","author":"Brockmueller","year":"2024","journal-title":"Cancer Metastasis Rev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e2728","DOI":"10.1038\/cddis.2017.152","article-title":"cPLA2\u03b1 mediates TGF-\u03b2-induced epithelial-mesenchymal transition in breast cancer through PI3k\/Akt signaling","volume":"8","author":"Chen","year":"2017","journal-title":"Cell Death Dis."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2210","DOI":"10.1007\/s12094-022-02882-z","article-title":"Resveratrol inhibits TGF-\u03b21-induced EMT in gastric cancer cells through Hippo-YAP signaling pathway","volume":"24","author":"Deng","year":"2022","journal-title":"Clin. Transl. Oncol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.3390\/biomedicines12112477","article-title":"SAR1A induces cell growth and epithelial-mesenchymal transition through the PI3K\/AKT\/mTOR pathway in head and neck squamous cell carcinoma: an in vitro and in vivo study","volume":"12","author":"Fang","year":"2024","journal-title":"Biomedicines"},{"key":"B6","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.cell.2017.07.029","article-title":"The PI3K pathway in human disease","volume":"170","author":"Fruman","year":"2017","journal-title":"Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.ejphar.2018.10.008","article-title":"Pterostilbene alleviates fructose-induced renal fibrosis by suppressing TGF-\u03b21\/TGF-\u03b2 type I receptor\/Smads signaling in proximal tubular epithelial cells","volume":"842","author":"Gu","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"232791","DOI":"10.1155\/2015\/232791","article-title":"Hypoxia-induced epithelial-mesenchymal transition is involved in bleomycin-induced lung fibrosis","volume":"2015","author":"Guo","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"B9","doi-asserted-by":"publisher","first-page":"155316","DOI":"10.1016\/j.phymed.2023.155316","article-title":"Pterostilbene suppresses gastric cancer proliferation and metastasis by inhibiting oncogenic JAK2\/STAT3 signaling: in vitro and in vivo therapeutic intervention","volume":"128","author":"He","year":"2024","journal-title":"Phytomedicine"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.3390\/biomedicines12071591","article-title":"Molecular Hydrogen Protects against various tissue Injuries from Side effects of Anticancer drugs by reducing oxidative stress and inflammation","volume":"12","author":"Hirano","year":"2024","journal-title":"Biomedicines"},{"key":"B11","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1159\/000494476","article-title":"Pinostilbene hydrate suppresses human oral cancer cell metastasis by downregulation of matrix Metalloproteinase-2 through the Mitogen-activated protein kinase signaling pathway","volume":"50","author":"Hsieh","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"B12","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1165\/rcmb.2017-0096ST","article-title":"An Official American Thoracic Society Workshop Report: use of animal models for the Preclinical assessment of potential therapies for pulmonary fibrosis","volume":"56","author":"Jenkins","year":"2017","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1007\/s10787-023-01416-5","article-title":"Quercetin attenuates Pseudomonas aeruginosa-induced acute lung inflammation by inhibiting PI3K\/AKT\/NF-\u03baB signaling pathway","volume":"32","author":"Jia","year":"2024","journal-title":"Inflammopharmacology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"160","DOI":"10.24976\/Discov.Med.202436180.15","article-title":"Tamoxifen alleviates endometrial fibrosis induced by Anhydrous Ethanol in Rats","volume":"36","author":"Jiang","year":"2024","journal-title":"Discov. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e2200146","DOI":"10.1002\/mnfr.202200146","article-title":"The anti-obesity and anti-inflammatory Capabilities of pterostilbene and its colonic metabolite pinostilbene Protect against tight junction disruption from western Diet Feeding","volume":"66","author":"Koh","year":"2022","journal-title":"Mol. Nutr. Food Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2937","DOI":"10.1111\/jcmm.13206","article-title":"Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the Src pathway","volume":"21","author":"Li","year":"2017","journal-title":"J. Cell Mol. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1021\/acs.jafc.2c05334","article-title":"Phase I metabolism of pterostilbene, a Dietary resveratrol Derivative: metabolite Identification, species differences, Isozyme contribution, and further bioactivation","volume":"71","author":"Li","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"117451","DOI":"10.1016\/j.ecoenv.2024.117451","article-title":"Bleomycin pollution and lung health: the therapeutic potential of peimine in bleomycin-induced pulmonary fibrosis by inhibiting glycolysis","volume":"289","author":"Li","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B19","doi-asserted-by":"publisher","first-page":"111301","DOI":"10.1016\/j.cellsig.2024.111301","article-title":"The positive role of transforming growth factor-\u03b21 in ischemic stroke","volume":"121","author":"Li","year":"2024","journal-title":"Cell Signal"},{"key":"B20","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1186\/s12964-024-01957-4","article-title":"The impact of epithelial-mesenchymal transition (EMT) induced by metabolic processes and intracellular signaling pathways on chemo-resistance, metastasis, and recurrence in solid tumors","volume":"22","author":"Liaghat","year":"2024","journal-title":"Cell Commun. Signal"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1248\/bpb.b22-00530","article-title":"Tamoxifen regulates epithelial-mesenchymal transition in endometrial cancer via the CANP10\/NRP1 signaling pathway","volume":"45","author":"Lv","year":"2022","journal-title":"Biol. Pharm. Bull."},{"key":"B22","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1080\/1120009x.2023.2300217","article-title":"Mechanisms underlying dose-limiting toxicities of conventional chemotherapeutic agents","volume":"36","author":"Manavi","year":"2024","journal-title":"J. Chemother."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.3390\/life14111431","article-title":"Mechanisms of microRNA regulation of the epithelial-mesenchymal transition (EMT) in lung cancer","volume":"14","author":"Mart\u00ednez-Espinosa","year":"2024","journal-title":"Life (Basel)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"105897","DOI":"10.1016\/j.archoralbio.2024.105897","article-title":"Resveratrol is an inhibitory polyphenol of epithelial-mesenchymal transition induced by Fusobacterium nucleatum","volume":"160","author":"Min","year":"2024","journal-title":"Arch. Oral Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1007\/s12013-024-01384-9","article-title":"Mechanisms of bleomycin-induced lung fibrosis: a review of therapeutic targets and approaches","volume":"82","author":"Mohammed","year":"2024","journal-title":"Cell Biochem. Biophys."},{"key":"B26","doi-asserted-by":"publisher","first-page":"20765","DOI":"10.1021\/acs.jmedchem.4c01885","article-title":"In silico Tools to Score and predict Cholesterol-protein interactions","volume":"67","author":"Nguyen","year":"2024","journal-title":"J. Med. Chem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s13020-021-00474-7","article-title":"Pterostilbene alleviates pulmonary fibrosis by regulating ASIC2","volume":"16","author":"Peng","year":"2021","journal-title":"Chin. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"113688","DOI":"10.1016\/j.intimp.2024.113688","article-title":"Effect of ethyl acetate extract of the whole plant Clerodendrum phlomidis on improving bleomycin (BLM)-induced idiopathic pulmonary fibrosis (IPF) in Rats: in vitro and in vivo research","volume":"145","author":"Sangaraju","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"107970","DOI":"10.1016\/j.bioorg.2024.107970","article-title":"In vivo, in vitro, and in silico approaches in the detailed study of di-butyl phthalate (DBP), a plasticizer-induced lung fibrosis via Nrf-2\/Keap-1\/HO-1 pathway and its regulation","volume":"154","author":"Singh","year":"2024","journal-title":"Bioorg Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.1111\/bph.14573","article-title":"Pterostilbene prevents hepatocyte epithelial-mesenchymal transition in fructose-induced liver fibrosis through suppressing miR-34a\/Sirt1\/p53 and TGF-\u03b21\/Smads signalling","volume":"176","author":"Song","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"582","DOI":"10.3724\/zdxbyxb-2021-0197","article-title":"Resveratrol inhibits the migration, invasion and epithelial-mesenchymal transition in liver cancer cells through up-miR-186-5p expression","volume":"50","author":"Song","year":"2021","journal-title":"Zhejiang Da Xue Xue Bao Yi Xue Ban."},{"key":"B32","doi-asserted-by":"publisher","first-page":"12590","DOI":"10.3390\/ijms241612590","article-title":"Cytotoxic and Apoptotic effects of pinostilbene and bortezomib combination treatment on human multiple myeloma cells","volume":"24","author":"Staskiewicz","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.1002\/mnfr.201500989","article-title":"Identification of pinostilbene as a major colonic metabolite of pterostilbene and its inhibitory effects on colon cancer cells","volume":"60","author":"Sun","year":"2016","journal-title":"Mol. Nutr. Food Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2274","DOI":"10.24976\/Discov.Med.202436190.209","article-title":"Angiotensin-converting enzyme 2 suppresses pulmonary fibrosis associated with Wnt and TGF-\u03b21 signaling pathways","volume":"36","author":"Tang","year":"2024","journal-title":"Discov. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2107","DOI":"10.2174\/0929867331666230914090053","article-title":"Resveratrol inhibits Hepatocellular carcinoma progression through regulating exosome secretion","volume":"31","author":"Tong","year":"2024","journal-title":"Curr. Med. Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"468","DOI":"10.3390\/biom9090468","article-title":"Antioxidant activity of selected stilbenoid Derivatives in a cellular model system","volume":"9","author":"Treml","year":"2019","journal-title":"Biomolecules"},{"key":"B37","doi-asserted-by":"publisher","first-page":"88","DOI":"10.3390\/antib13040088","article-title":"Anti-MET antibody therapies in Non-small-cell lung cancer: current progress and Future Directions","volume":"13","author":"Wang","year":"2024","journal-title":"Antibodies (Basel)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"114522","DOI":"10.1016\/j.jep.2021.114522","article-title":"Antifibrotic effect of Gancao Ganjiang decoction is mediated by PD-1\/TGF-\u03b21\/IL-17A pathway in bleomycin-induced idiopathic pulmonary fibrosis","volume":"281","author":"Wang","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1002\/ptr.7608","article-title":"Resveratrol reverses TGF-\u03b21-mediated invasion and metastasis of breast cancer cells via the SIRT3\/AMPK\/autophagy signal axis","volume":"37","author":"Wang","year":"2023","journal-title":"Phytother. Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"529","DOI":"10.2147\/bctt.S325429","article-title":"TGF-\u03b2-Induced TMEPAI promotes epithelial-mesenchymal transition in doxorubicin-treated Triple-negative breast cancer cells via SMAD3 and PI3K\/AKT pathway alteration","volume":"13","author":"Wardhani","year":"2021","journal-title":"Breast Cancer (Dove Med. Press)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"e1800657","DOI":"10.1002\/cbdv.201800657","article-title":"Dinorcassane Diterpenoid from Boesenbergia rotunda Rhizomes Collected in lower Myanmar","volume":"16","author":"Win","year":"2019","journal-title":"Chem. Biodivers."},{"key":"B42","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1007\/s00408-024-00764-5","article-title":"Disulfiram alleviates MTX-induced pulmonary fibrosis by inhibiting EMT in type 2 alveolar epithelial cells","volume":"203","author":"Wu","year":"2024","journal-title":"Lung"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e10238","DOI":"10.1016\/j.heliyon.2022.e10238","article-title":"High-content screening of active components of Traditional Chinese Medicine inhibiting TGF-\u03b2-induced cell EMT","volume":"8","author":"Xu","year":"2022","journal-title":"Heliyon"},{"key":"B44","doi-asserted-by":"publisher","first-page":"151181","DOI":"10.1016\/j.ejcb.2021.151181","article-title":"ROS-Nrf2 pathway mediates the development of TGF-\u03b21-induced epithelial-mesenchymal transition through the activation of Notch signaling","volume":"100","author":"Yazaki","year":"2021","journal-title":"Eur. J. Cell Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2887","DOI":"10.3892\/or.2016.4664","article-title":"Rhapontigenin inhibits TGF-\u03b2-mediated epithelial-mesenchymal transition via the PI3K\/AKT\/mTOR pathway and is not associated with HIF-1\u03b1 degradation","volume":"35","author":"Yeh","year":"2016","journal-title":"Oncol. Rep."},{"key":"B46","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s12906-019-2807-y","article-title":"Buyang Huanwu Tang inhibits cellular epithelial-to-mesenchymal transition by inhibiting TGF-\u03b21 activation of PI3K\/Akt signaling pathway in pulmonary fibrosis model in vitro","volume":"20","author":"Yin","year":"2020","journal-title":"BMC Complement. Med. Ther."},{"key":"B47","doi-asserted-by":"publisher","first-page":"117714","DOI":"10.1016\/j.biopha.2024.117714","article-title":"Decoding tumor microenvironment: EMT modulation in breast cancer metastasis and therapeutic resistance, and implications of novel immune checkpoint blockers","volume":"181","author":"Yuan","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"B48","doi-asserted-by":"publisher","first-page":"72","DOI":"10.3760\/cma.j.cn121094-20210628-00308","article-title":"Research progress of anti-fibrotic drugs that inhibit epithelial-mesenchymal transition in pulmonary fibrosis","volume":"41","author":"Zhang","year":"","journal-title":"Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi"},{"key":"B49","doi-asserted-by":"publisher","first-page":"149118","DOI":"10.1016\/j.bbrc.2023.10.050","article-title":"Cytokines as drivers: Unraveling the mechanisms of epithelial-mesenchymal transition in COVID-19 lung fibrosis","volume":"686","author":"Zhang","year":"","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B50","doi-asserted-by":"publisher","first-page":"106989","DOI":"10.1016\/j.ultsonch.2024.106989","article-title":"Ultrasonic extraction and antioxidant evaluation of oat saponins","volume":"109","author":"Zhang","year":"2024","journal-title":"Ultrason. Sonochem"},{"key":"B51","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.toxlet.2014.10.013","article-title":"Phenylbutyric acid inhibits epithelial-mesenchymal transition during bleomycin-induced lung fibrosis","volume":"232","author":"Zhao","year":"2015","journal-title":"Toxicol. Lett."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1614546\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T05:32:23Z","timestamp":1757050343000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1614546\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,5]]},"references-count":51,"alternative-id":["10.3389\/fphar.2025.1614546"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1614546","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,5]]},"article-number":"1614546"}}