{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T05:19:02Z","timestamp":1787548742819,"version":"build-2736575974"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The renin-angiotensin system (RAS), a pivotal target in gastric ulcers, has been shown to regulate ferroptosis in bronchial epithelial cells. Rosmarinic acid (RA) possesses significant anti-ulcer and anti-ferroptosis effects. However, it is still unclear whether RA alleviates gastric ulcers by preventing ferroptosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used a water restraint-induced ulcer mouse model, and an LPS-induced GEC-1 cells inflammation model to observe stress-induced damage both\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      , and to explore the protective effects and mechanisms of RA on such damage.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified 14 DEGs related to ferroptosis between chronic gastritis and gastric ulcer. Some form a PPI network with RAS-related protein and serum ACE2 was significantly increased in ulcers. Molecular docking and molecular dynamics simulations revealed stable binding between GPX4 and ACE2, and the incorporation of RA markedly boosts its stability. Also, RA administration significantly mitigated SGU via upregulation of GPX4 and ACE2 in cold water-immersion restraint stress (CWIR) mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our research demonstrates that RA may be a therapeutic strategy to improve SGU by targeting the ACE2\/GPX4 interaction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1891305","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T04:23:35Z","timestamp":1787545415000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Rosmarinic acid mitigates stress-induced gastric ulcers by targeting the ACE2\/GPX4 interaction"],"prefix":"10.3389","volume":"17","author":[{"given":"Tao","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei-yang","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-qiang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, 363 Hospital","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-wen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-fu","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-hong","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruo-ting","family":"Men","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, West China Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-hui","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, West China Hospital, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-hong","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/s00134-019-05526-z","article-title":"Stress ulcer prophylaxis with proton pump inhibitors or histamin-2 receptor antagonists in adult intensive care patients: a systematic review with meta-analysis and trial sequential analysis","volume":"45","author":"Barbateskovic","year":"2019","journal-title":"Intensive Care Medicine"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3910","DOI":"10.2174\/1381612823666170220160222","article-title":"Recent advances in the gastric mucosal protection against stress-induced gastric lesions. Importance of renin-angiotensin vasoactive metabolites, gaseous mediators and appetite peptides","volume":"23","author":"Brzozowski","year":"2017","journal-title":"Curr. Pharmaceutical Design"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2265","DOI":"10.1007\/s00210-020-01894-2","article-title":"Rosmarinic acid prevents gastric ulcers via sulfhydryl groups reinforcement, antioxidant and immunomodulatory effects","volume":"393","author":"do Nascimento","year":"2020","journal-title":"Naunyn-Schmiedeberg's Archives Pharmacology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1161\/CIRCRESAHA.119.315743","article-title":"Bone marrow-derived cells restore functional integrity of the gut epithelial and vascular barriers in a model of diabetes and ACE2 deficiency","volume":"125","author":"Duan","year":"2019","journal-title":"Circulation Research"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1161\/CIRCRESAHA.120.317015","article-title":"Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2","volume":"126","author":"Gheblawi","year":"2020","journal-title":"Circulation Research"},{"key":"B6","doi-asserted-by":"publisher","first-page":"3928","DOI":"10.2174\/1381612823666161118144216","article-title":"Stress, neuropeptides and gastric mucosa","volume":"23","author":"Gyires","year":"2017","journal-title":"Curr. Pharmaceutical Design"},{"key":"B7","doi-asserted-by":"publisher","first-page":"9514703","DOI":"10.1155\/2019\/9514703","article-title":"Rosmarinic acid enriched fraction from Perilla frutescens leaves strongly protects indomethacin-induced gastric ulcer in rats","volume":"2019","author":"Kangwan","year":"2019","journal-title":"BioMed Research International"},{"key":"B8","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.therap.2020.06.019","article-title":"Long-term use of proton pump inhibitors as a risk factor for various adverse manifestations","volume":"76","author":"Koyyada","year":"2021","journal-title":"Therapie"},{"key":"B9","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1111\/aas.12508","article-title":"Stress ulcer prophylaxis in the intensive care unit: an international survey of 97 units in 11 countries","volume":"59","author":"Krag","year":"2015","journal-title":"Acta Anaesthesiologica Scand."},{"key":"B10","doi-asserted-by":"publisher","first-page":"30113","DOI":"10.1074\/jbc.M505111200","article-title":"Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)","volume":"280","author":"Lambert","year":"2005","journal-title":"J. Biological Chemistry"},{"key":"B11","doi-asserted-by":"publisher","first-page":"39","DOI":"10.2147\/DDDT.S481646","article-title":"Protective effect of rosmarinic acid on endotoxin-induced neuronal damage through modulating GRP78\/PERK\/MANF pathway","volume":"19","author":"Li","year":"2025","journal-title":"Drug Design, Development Therapy"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.26599\/FSHW.2026.9251121","article-title":"Rosmarinic acid, the key dietary antioxidant in rosmarinus officinalis L. identified by integrated screening, targets PPAR\u03b3 to activate Nrf2\/NQO1 axis and mitigate oxidative stress","volume":"16","author":"Liang","year":"2026","journal-title":"Food Sci. Hum. Wellness"},{"key":"B13","doi-asserted-by":"publisher","first-page":"9998982","DOI":"10.1155\/2021\/9998982","article-title":"Protective effects of anwulignan against HCl\/ethanol-induced acute gastric ulcer in mice","volume":"2021","author":"Liu","year":"2021","journal-title":"Evidence-based Complementary Alternative Medicine eCAM"},{"key":"B14","first-page":"749","article-title":"The effect of hydrogen sulfide-releasing naproxen (ATB-346) versus naproxen on formation of stress-induced gastric lesions, the regulation of systemic inflammation, hypoxia and alterations in gastric microcirculation","volume":"68","author":"Magierowski","year":"2017","journal-title":"J. Physiology Pharmacology An Official Journal Pol. Physiological Soc."},{"key":"B15","doi-asserted-by":"publisher","first-page":"116440","DOI":"10.1016\/j.bcp.2024.116440","article-title":"Lamivudine protects mice from gastric ulcer by activating PGK1 to suppress ferroptosis","volume":"227","author":"Meng","year":"2024","journal-title":"Biochem. Pharmacology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/s12272-022-01378-2","article-title":"Biomedical features and therapeutic potential of rosmarinic acid","volume":"45","author":"Noor","year":"2022","journal-title":"Archives Pharmacal Research"},{"key":"B17","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1080\/13813455.2022.2080228","article-title":"High prevalence of SARS-Coronavirus-2 in patients with inflammatory bowel disease and the role of soluble angiotensin converting enzyme 2","volume":"130","author":"Shahrokh","year":"2024","journal-title":"Archives Physiology Biochemistry"},{"key":"B18","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.bcp.2016.05.010","article-title":"Diminazene aceturate, an angiotensin-converting enzyme II activator, prevents gastric mucosal damage in mice: role of the angiotensin-(1-7)\/Mas receptor axis","volume":"112","author":"Souza","year":"2016","journal-title":"Biochem. Pharmacology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell."},{"key":"B20","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1530\/JOE-19-0030","article-title":"Local gastric RAAS inhibition improves gastric microvascular perfusion in dogs","volume":"241","author":"Truse","year":"2019","journal-title":"J. Endocrinology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1111\/bcpt.13944","article-title":"BCPT 2023 policy for experimental and clinical studies","volume":"133","author":"Tveden-Nyborg","year":"2023","journal-title":"Basic and Clinical Pharmacology and Toxicology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1586\/17474124.3.1.15","article-title":"Esomeprazole: a proton pump inhibitor","volume":"3","author":"Vachhani","year":"2009","journal-title":"Expert Review Gastroenterology and Hepatology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"253","DOI":"10.3390\/antiox14030253","article-title":"Impact of glucose, inflammation and phytochemicals on ACE2, TMPRSS2 and glucose transporter gene expression in human intestinal cells","volume":"14","author":"Visvanathan","year":"2025","journal-title":"Antioxidants Basel, Switz."},{"key":"B24","doi-asserted-by":"publisher","first-page":"153382","DOI":"10.1016\/j.phymed.2020.153382","article-title":"Protective effect of rosmarinic acid-rich trichodesma khasianum clarke leaves against ethanol-induced gastric mucosal injury in vitro and in vivo","volume":"80","author":"Wang","year":"2021","journal-title":"Phytomedicine International Journal Phytotherapy Phytopharmacology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1159\/000538245","article-title":"Plasma soluble angiotensin-converting enzyme 2 and risk of recurrent stroke: a nested case-control analysis","volume":"54","author":"Xue","year":"2025","journal-title":"Cerebrovasc. Diseases Basel, Switz."},{"key":"B26","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.cell.2013.12.010","article-title":"Regulation of ferroptotic cancer cell death by GPX4","volume":"156","author":"Yang","year":"2014","journal-title":"Cell."},{"key":"B27","doi-asserted-by":"publisher","first-page":"49148","DOI":"10.31083\/FBL49148","article-title":"Gender differences in the effects of esomeprazole on ethanol-induced acute gastric injury in mice","volume":"31","author":"Yi","year":"2026","journal-title":"Front. Biosci. Landmark Ed."},{"key":"B28","doi-asserted-by":"publisher","first-page":"112304","DOI":"10.1016\/j.intimp.2024.112304","article-title":"Rosmarinic acid alleviates septic acute respiratory distress syndrome in mice by suppressing the bronchial epithelial RAS-mediated ferroptosis","volume":"135","author":"Zeng","year":"2024","journal-title":"Int. Immunopharmacology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"109621","DOI":"10.1016\/j.abb.2023.109621","article-title":"ALDH2 ameliorates ethanol-induced gastric ulcer through suppressing NLPR3 inflammasome activation and ferroptosis","volume":"743","author":"Zhang","year":"2023","journal-title":"Archives Biochemistry Biophysics"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1891305\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T04:23:36Z","timestamp":1787545416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1891305\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":29,"alternative-id":["10.3389\/fphar.2026.1891305"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1891305","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,24]]},"article-number":"1891305"}}