{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T02:02:44Z","timestamp":1789956164370,"version":"4.0.1"},"reference-count":25,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770399"],"award-info":[{"award-number":["81770399"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82400282"],"award-info":[{"award-number":["82400282"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Cardiac hypertrophy is a major pathological response to cardiovascular stress and a critical contributor to heart failure (HF). Gentiopicroside (GPS), a naturally occurring iridoid glycoside derived from Gentiana scabra, exhibits anti\u2010inflammatory, antioxidant, and anti\u2010fibrotic properties. However, its role and molecular mechanisms in cardiac hypertrophy and HF remain unclear. A pressure overload\u2010induced cardiac remodeling model was established in C57BL\/6 mice by transverse aortic constriction (TAC), followed by GPS treatment with or without the EGFR tyrosine kinase inhibitor Canertinib. Cardiac function and remodeling were evaluated by echocardiography, hemodynamic analysis, and histological staining. In\u00a0vitro, neonatal rat ventricular myocytes (NRVMs) and cardiac fibroblasts (NRCFs) were used to investigate the cellular effects of GPS. EGFR knockdown, conditioned medium transfer, cellular thermal shift assay (CETSA), and lysosomal\/proteasomal inhibition experiments were performed to elucidate the mechanism underlying GPS\u2010mediated EGFR regulation. GPS markedly alleviated TAC\u2010induced cardiac hypertrophy and fibrosis in\u00a0vivo and suppressed Ang II\u2010induced cardiomyocyte hypertrophy. GPS also reduced cardiomyocyte apoptosis and oxidative stress. Mechanistically, GPS acted as an EGFR degrader rather than a conventional kinase inhibitor, reducing total EGFR abundance without inhibiting the kinase activity of remaining receptors, thereby attenuating excessive AKT\/ERK1\/2 signaling. CETSA and molecular docking indicated direct GPS\u2013EGFR interaction. GPS\u2010induced EGFR reduction was mediated primarily through lysosomal degradation, as demonstrated by chloroquine rescue experiments, whereas proteasome inhibition had limited effects. Co\u2010administration of Canertinib with GPS conferred no additional benefit. EGFR depletion abolished the protective effect of GPS in cardiomyocytes, indicating a cardiomyocyte\u2010autonomous mechanism. This study identifies GPS as a regulator of EGFR stability during pathological cardiac remodeling. By promoting lysosome\u2010dependent EGFR degradation and suppressing excessive AKT\/ERK1\/2 signaling, GPS attenuates cardiac hypertrophy and remodeling while preserving basal EGFR function, highlighting its potential therapeutic value for HF.<\/jats:p>","DOI":"10.1002\/ptr.70452","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T01:46:37Z","timestamp":1789955197000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gentiopicroside Regulates\n                    <scp>EGFR<\/scp>\n                    and Induces Its Lysosomal Degradation to Attenuate Heart Failure"],"prefix":"10.1002","author":[{"given":"Mingzhen","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da","family":"Ke","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6690-4449","authenticated-orcid":false,"given":"Zhang","family":"Nan","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiujun","family":"Dai","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9599-2499","authenticated-orcid":false,"given":"Heng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"issue":"2","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1021\/jacs.3c10132","article-title":"Lipid Peroxidation Drives Liquid\u2010Liquid Phase Separation and Disrupts Raft Protein Partitioning in Biological Membranes","volume":"146","author":"Balakrishnan M.","year":"2024","journal-title":"Journal of the American Chemical Society"},{"issue":"5","key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1093\/cvr\/cvae045","article-title":"Large Animal Models of Pressure Overload\u2010Induced Cardiac Left Ventricular Hypertrophy to Study Remodelling of the Human Heart With Aortic Stenosis","volume":"120","author":"Beslika E.","year":"2024","journal-title":"Cardiovascular Research"},{"issue":"16","key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"eaax4826","DOI":"10.1126\/sciadv.aax4826","article-title":"The Deubiquitinase UCHL1 Regulates Cardiac Hypertrophy by Stabilizing Epidermal Growth Factor Receptor","volume":"6","author":"Bi H. L.","year":"2020","journal-title":"Science Advances"},{"issue":"1","key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1038\/s41467-024-45443-4","article-title":"Phosphoglycerate Kinase 1 Acts as a Cargo Adaptor to Promote EGFR Transport to the Lysosome","volume":"15","author":"Chu S. L.","year":"2024","journal-title":"Nature Communications"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.jare.2025.05.039","article-title":"Targeting the Bile Acid Receptor TGR5 With Gentiopicroside to Activate Nrf2 Antioxidant Signaling and Mitigate Parkinson's Disease in an MPTP Mouse Model","volume":"80","author":"Gao Y.","year":"2025","journal-title":"Journal of Advanced Research"},{"issue":"5","key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1093\/cvr\/cvab149","article-title":"Epidermal Growth Factor Receptor\u2010Dependent Maintenance of Cardiac Contractility","volume":"118","author":"Guo S.","year":"2022","journal-title":"Cardiovascular Research"},{"issue":"23","key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"2923","DOI":"10.1016\/j.jacc.2021.04.028","article-title":"AntimiR\u2010132 Attenuates Myocardial Hypertrophy in an Animal Model of Percutaneous Aortic Constriction","volume":"77","author":"Hinkel R.","year":"2021","journal-title":"Journal of the American College of Cardiology"},{"issue":"10","key":"e_1_2_11_9_1","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1161\/CIRCRESAHA.123.323517","article-title":"MRP1\u2010Dependent Extracellular Release of Glutathione Induces Cardiomyocyte Ferroptosis After Ischemia\u2010Reperfusion","volume":"133","author":"Ichihara G.","year":"2023","journal-title":"Circulation Research"},{"issue":"5","key":"e_1_2_11_10_1","doi-asserted-by":"crossref","first-page":"e143173","DOI":"10.1172\/JCI143173","article-title":"YAP Plays a Crucial Role in the Development of Cardiomyopathy in Lysosomal Storage Diseases","volume":"131","author":"Ikeda S.","year":"2021","journal-title":"Journal of Clinical Investigation"},{"issue":"12","key":"e_1_2_11_11_1","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1161\/HYPERTENSIONAHA.123.21427","article-title":"ESCRT\u2010III Component CHMP4C Attenuates Cardiac Hypertrophy by Targeting the Endo\u2010Lysosomal Degradation of EGFR","volume":"80","author":"Liu A.","year":"2023","journal-title":"Hypertension"},{"issue":"32","key":"e_1_2_11_12_1","doi-asserted-by":"crossref","first-page":"e2309560","DOI":"10.1002\/advs.202309560","article-title":"E3 Ubiquitin Ligase RNF13 Suppresses TLR Lysosomal Degradation by Promoting LAMP\u20101 Proteasomal Degradation","volume":"11","author":"Liu W.","year":"2024","journal-title":"Advanced Science"},{"issue":"10","key":"e_1_2_11_13_1","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1161\/CIRCRESAHA.123.323882","article-title":"Inhibition of the mPTP and Lipid Peroxidation Is Additively Protective Against I\/R Injury","volume":"134","author":"Mendoza A.","year":"2024","journal-title":"Circulation Research"},{"issue":"11","key":"e_1_2_11_14_1","first-page":"e006170","article-title":"Mitochondrial Reversible Changes Determine Diastolic Function Adaptations During Myocardial (Reverse) Remodeling","volume":"13","author":"Miranda\u2010Silva D.","year":"2020","journal-title":"Circulation: Heart Failure"},{"issue":"1","key":"e_1_2_11_15_1","doi-asserted-by":"crossref","first-page":"4498","DOI":"10.1038\/s41467-023-40268-z","article-title":"Cysteines 1078 and 2991 Cross\u2010Linking Plays a Critical Role in Redox Regulation of Cardiac Ryanodine Receptor (RyR)","volume":"14","author":"Nikolaienko R.","year":"2023","journal-title":"Nature Communications"},{"issue":"1","key":"e_1_2_11_16_1","doi-asserted-by":"crossref","first-page":"6112","DOI":"10.1038\/s41467-022-33881-x","article-title":"Spatial Snapshots of Amyloid Precursor Protein Intramembrane Processing via Early Endosome Proteomics","volume":"13","author":"Park H.","year":"2022","journal-title":"Nature Communications"},{"issue":"3","key":"e_1_2_11_17_1","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1007\/s11906-006-0056-1","article-title":"Reactive Oxygen Species in the Neuropathogenesis of Hypertension","volume":"8","author":"Peterson J. R.","year":"2006","journal-title":"Current Hypertension Reports"},{"issue":"9","key":"e_1_2_11_18_1","doi-asserted-by":"crossref","first-page":"846","DOI":"10.3390\/antiox9090846","article-title":"Beneficial Effects of Glucagon\u2010Like Peptide\u20101 (GLP\u20101) in Diabetes\u2010Induced Retinal Abnormalities: Involvement of Oxidative Stress","volume":"9","author":"Ramos H.","year":"2020","journal-title":"Antioxidants"},{"issue":"6","key":"e_1_2_11_19_1","doi-asserted-by":"crossref","first-page":"e163763","DOI":"10.1172\/jci.insight.163763","article-title":"EGFR Inhibition Leads to Enhanced Desmosome Assembly and Cardiomyocyte Cohesion via ROCK Activation","volume":"8","author":"Shoykhet M.","year":"2023","journal-title":"JCI Insight"},{"issue":"329","key":"e_1_2_11_20_1","doi-asserted-by":"crossref","first-page":"121973","DOI":"10.1016\/j.lfs.2023.121973","article-title":"Tissue Kallikrein\u2010Related peptidase8 Accentuates Cardiac Fibrosis After Myocardial Ischemia\u2010Reperfusion Injury via Regulation of Cardiac Fibroblasts","volume":"15","author":"Song J.","year":"2023","journal-title":"Life Sciences"},{"issue":"5","key":"e_1_2_11_21_1","doi-asserted-by":"crossref","first-page":"e2204999","DOI":"10.1002\/advs.202204999","article-title":"A Self\u2010Sustaining Antioxidant Strategy for Effective Treatment of Myocardial Infarction","volume":"10","author":"Sun Q.","year":"2023","journal-title":"Advanced Science"},{"issue":"14","key":"e_1_2_11_22_1","doi-asserted-by":"crossref","first-page":"6753","DOI":"10.7150\/thno.104124","article-title":"RAB7 Protects Against Ischemic Heart Failure via Promoting Non\u2010Canonical TUFM Mitophagy Pathway","volume":"15","author":"Sun Y.","year":"2025","journal-title":"Theranostics"},{"issue":"6","key":"e_1_2_11_23_1","doi-asserted-by":"crossref","first-page":"2887","DOI":"10.1016\/j.apsb.2021.12.023","article-title":"Gentiopicroside Targets PAQR3 to Activate the PI3K\/AKT Signaling Pathway and Ameliorate Disordered Glucose and Lipid Metabolism","volume":"12","author":"Xiao H.","year":"2022","journal-title":"Acta Pharmaceutica Sinica B"},{"issue":"1","key":"e_1_2_11_24_1","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1038\/s42003-022-04021-4","article-title":"Alteration in Tyrosine Phosphorylation of Cardiac Proteome and EGFR Pathway Contribute to Hypertrophic Cardiomyopathy","volume":"5","author":"Xu M.","year":"2022","journal-title":"Communications Biology"},{"issue":"1","key":"e_1_2_11_25_1","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1186\/s12951-024-02796-8","article-title":"Ellagic Acid\u2010Enhanced Biocompatibility and Bioactivity in Multilayer Core\u2010Shell Gold Nanoparticles for Ameliorating Myocardial Infarction Injury","volume":"22","author":"Yu X.","year":"2024","journal-title":"Journal of Nanobiotechnology"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201031992\u2010z"}],"container-title":["Phytotherapy Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70452","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ptr.70452","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70452","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T01:46:40Z","timestamp":1789955200000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ptr.70452"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,20]]},"references-count":25,"alternative-id":["10.1002\/ptr.70452"],"URL":"https:\/\/doi.org\/10.1002\/ptr.70452","archive":["Portico"],"relation":{},"ISSN":["0951-418X","1099-1573"],"issn-type":[{"value":"0951-418X","type":"print"},{"value":"1099-1573","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,20]]},"assertion":[{"value":"2025-08-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"ptr.70452"}}