{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T05:07:54Z","timestamp":1776488874029,"version":"3.51.2"},"reference-count":22,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82030007"],"award-info":[{"award-number":["82030007"]}]},{"name":"National Natural Science Foundation of China","award":["U23A20398"],"award-info":[{"award-number":["U23A20398"]}]},{"name":"National Natural Science Foundation of China","award":["2024ZD0537707"],"award-info":[{"award-number":["2024ZD0537707"]}]},{"name":"National Natural Science Foundation of China","award":["2023NSFSC1675"],"award-info":[{"award-number":["2023NSFSC1675"]}]},{"name":"National Natural Science Foundation of China","award":["2022YFS0578"],"award-info":[{"award-number":["2022YFS0578"]}]},{"name":"National Natural Science Foundation of China","award":["2022YFS0614"],"award-info":[{"award-number":["2022YFS0614"]}]},{"name":"National Natural Science Foundation of China","award":["20230004-01SZ"],"award-info":[{"award-number":["20230004-01SZ"]}]},{"name":"National Natural Science Foundation of China","award":["2022QN001"],"award-info":[{"award-number":["2022QN001"]}]},{"name":"National Natural Science Foundation of China","award":["2023JYJ006"],"award-info":[{"award-number":["2023JYJ006"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["82030007"],"award-info":[{"award-number":["82030007"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["U23A20398"],"award-info":[{"award-number":["U23A20398"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2024ZD0537707"],"award-info":[{"award-number":["2024ZD0537707"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2023NSFSC1675"],"award-info":[{"award-number":["2023NSFSC1675"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2022YFS0578"],"award-info":[{"award-number":["2022YFS0578"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2022YFS0614"],"award-info":[{"award-number":["2022YFS0614"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["20230004-01SZ"],"award-info":[{"award-number":["20230004-01SZ"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2022QN001"],"award-info":[{"award-number":["2022QN001"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2023JYJ006"],"award-info":[{"award-number":["2023JYJ006"]}]},{"name":"the Natural Science Foundation of Sichuan","award":["82030007"],"award-info":[{"award-number":["82030007"]}]},{"name":"the Natural Science Foundation of Sichuan","award":["U23A20398"],"award-info":[{"award-number":["U23A20398"]}]},{"name":"the Natural Science Foundation of Sichuan","award":["2024ZD0537707"],"award-info":[{"award-number":["2024ZD0537707"]}]},{"name":"the Natural Science Foundation of Sichuan","award":["2023NSFSC1675"],"award-info":[{"award-number":["2023NSFSC1675"]}]},{"name":"the Natural Science Foundation of Sichuan","award":["2022YFS0578"],"award-info":[{"award-number":["2022YFS0578"]}]},{"name":"the Natural Science Foundation of Sichuan","award":["2022YFS0614"],"award-info":[{"award-number":["2022YFS0614"]}]},{"name":"the Natural Science Foundation of Sichuan","award":["20230004-01SZ"],"award-info":[{"award-number":["20230004-01SZ"]}]},{"name":"the Natural Science Foundation of Sichuan","award":["2022QN001"],"award-info":[{"award-number":["2022QN001"]}]},{"name":"the Natural Science Foundation of Sichuan","award":["2023JYJ006"],"award-info":[{"award-number":["2023JYJ006"]}]},{"name":"the Central Nervous System Drug Key Laboratory of Sichuan Province","award":["82030007"],"award-info":[{"award-number":["82030007"]}]},{"name":"the Central Nervous System Drug Key Laboratory of Sichuan Province","award":["U23A20398"],"award-info":[{"award-number":["U23A20398"]}]},{"name":"the Central Nervous System Drug Key Laboratory of Sichuan Province","award":["2024ZD0537707"],"award-info":[{"award-number":["2024ZD0537707"]}]},{"name":"the Central Nervous System Drug Key Laboratory of Sichuan Province","award":["2023NSFSC1675"],"award-info":[{"award-number":["2023NSFSC1675"]}]},{"name":"the Central Nervous System Drug Key Laboratory of Sichuan Province","award":["2022YFS0578"],"award-info":[{"award-number":["2022YFS0578"]}]},{"name":"the Central Nervous System Drug Key Laboratory of Sichuan Province","award":["2022YFS0614"],"award-info":[{"award-number":["2022YFS0614"]}]},{"name":"the Central Nervous System Drug Key Laboratory of Sichuan Province","award":["20230004-01SZ"],"award-info":[{"award-number":["20230004-01SZ"]}]},{"name":"the Central Nervous System Drug Key Laboratory of Sichuan Province","award":["2022QN001"],"award-info":[{"award-number":["2022QN001"]}]},{"name":"the Central Nervous System Drug Key Laboratory of Sichuan Province","award":["2023JYJ006"],"award-info":[{"award-number":["2023JYJ006"]}]},{"name":"Southwest Medical Universit","award":["82030007"],"award-info":[{"award-number":["82030007"]}]},{"name":"Southwest Medical Universit","award":["U23A20398"],"award-info":[{"award-number":["U23A20398"]}]},{"name":"Southwest Medical Universit","award":["2024ZD0537707"],"award-info":[{"award-number":["2024ZD0537707"]}]},{"name":"Southwest Medical Universit","award":["2023NSFSC1675"],"award-info":[{"award-number":["2023NSFSC1675"]}]},{"name":"Southwest Medical Universit","award":["2022YFS0578"],"award-info":[{"award-number":["2022YFS0578"]}]},{"name":"Southwest Medical Universit","award":["2022YFS0614"],"award-info":[{"award-number":["2022YFS0614"]}]},{"name":"Southwest Medical Universit","award":["20230004-01SZ"],"award-info":[{"award-number":["20230004-01SZ"]}]},{"name":"Southwest Medical Universit","award":["2022QN001"],"award-info":[{"award-number":["2022QN001"]}]},{"name":"Southwest Medical Universit","award":["2023JYJ006"],"award-info":[{"award-number":["2023JYJ006"]}]},{"name":"the Science and Technology Project of Luzhou Government","award":["82030007"],"award-info":[{"award-number":["82030007"]}]},{"name":"the Science and Technology Project of Luzhou Government","award":["U23A20398"],"award-info":[{"award-number":["U23A20398"]}]},{"name":"the Science and Technology Project of Luzhou Government","award":["2024ZD0537707"],"award-info":[{"award-number":["2024ZD0537707"]}]},{"name":"the Science and Technology Project of Luzhou Government","award":["2023NSFSC1675"],"award-info":[{"award-number":["2023NSFSC1675"]}]},{"name":"the Science and Technology Project of Luzhou Government","award":["2022YFS0578"],"award-info":[{"award-number":["2022YFS0578"]}]},{"name":"the Science and Technology Project of Luzhou Government","award":["2022YFS0614"],"award-info":[{"award-number":["2022YFS0614"]}]},{"name":"the Science and Technology Project of Luzhou Government","award":["20230004-01SZ"],"award-info":[{"award-number":["20230004-01SZ"]}]},{"name":"the Science and Technology Project of Luzhou Government","award":["2022QN001"],"award-info":[{"award-number":["2022QN001"]}]},{"name":"the Science and Technology Project of Luzhou Government","award":["2023JYJ006"],"award-info":[{"award-number":["2023JYJ006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Sepsis-induced cardiomyopathy is a life-threatening complication lacking targeted therapies. While empagliflozin (Empa), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, confers robust cardioprotection, its specific efficacy in treating sepsis-induced cardiomyopathy and the Empa mechanisms remain poorly defined, limiting its targeted therapeutic use. In this study, we investigated Empa\u2019s effects and its novel mechanisms in a murine lipopolysaccharide (LPS)-induced model of septic cardiomyopathy. Empa pre-treatment effectively prevented LPS-induced cardiac dysfunction, preserving ejection fraction and mitigating myocardial injury (assessed by histology and ELISA) and fibrosis. Transcriptomic analysis revealed that Empa\u2019s protective effects were profoundly linked to the preservation of cardiomyocyte cytoskeletal pathways, alongside its anti-inflammatory actions. The results indicate that LPS induced a pathological dissociation of the matrix protein Integrin \u03b15 (ITGA5) from the cell\u2013cell adhesion protein Desmocollin-2 (DSC2), a structural disruption completely abrogated by Empa in vivo. This ITGA5-DSC2 stabilization was further confirmed to be a cardiomyocyte-intrinsic effect, recapitulated in vitro in both neonatal mouse cardiomyocytes and human AC16 cells. Building on this mechanistic insight, a computational design was successfully employed to develop 13 novel helical protein binders specifically targeting the ITGA5, yielding candidates with favorable structural properties as potential therapeutic leads. These findings establish the cardiomyocyte structural homeostasis via the ITGA5-DSC2 adhesion axis as a novel, key SGLT2-independent mechanism for empagliflozin\u2019s cardioprotection, revealing promising new therapeutic approaches for sepsis-induced cardiomyopathy.<\/jats:p>","DOI":"10.3390\/cells14181452","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T14:31:41Z","timestamp":1758033101000},"page":"1452","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Empagliflozin Preserves Cardiomyocyte Structural Homeostasis via the Stabilization of the Integrin \u03b15\u2013Desmocollin-2 Adhesion Axis in Sepsis-Induced Cardiomyopathy"],"prefix":"10.3390","volume":"14","author":[{"given":"Gan","family":"Qiao","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China"},{"name":"Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongxiang","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianping","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5708-0641","authenticated-orcid":false,"given":"Chunyang","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minghua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sicheng","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3308-0265","authenticated-orcid":false,"given":"Chunxiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China"},{"name":"Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Institute of Cardiovascular Research, Key Laboratory of Medical Electrophysiology, Ministry of Education, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan 646000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s11886-020-01277-2","article-title":"Sepsis-Induced Cardiomyopathy: A Comprehensive Review","volume":"22","author":"Sternberg","year":"2020","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Aissaoui, N., Boissier, F., Chew, M., Singer, M., and Vignon, P. (2025). Sepsis-Induced Cardiomyopathy. Eur. Heart J., ehaf340.","DOI":"10.1093\/eurheartj\/ehaf340"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Karakasis, P., Patoulias, D., Theofilis, P., Pamporis, K., Sagris, M., Vlachakis, P.K., Koufakis, T., Antoniadis, A.P., and Fragakis, N. (2025). GLP-1 Receptor Agonists and Myocardial Perfusion: Bridging Mechanisms to Clinical Outcomes. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26073050"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1002\/ehf2.13406","article-title":"Design and Rationale of the EMPA-VISION Trial: Investigating the Metabolic Effects of Empagliflozin in Patients with Heart Failure","volume":"8","author":"Hundertmark","year":"2021","journal-title":"ESC Heart Fail."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1007\/s13300-017-0320-1","article-title":"SGLT2 Inhibitors Through the Windows of EMPA-REG and CANVAS Trials: A Review","volume":"8","author":"Rastogi","year":"2017","journal-title":"Diabetes Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1161\/CIRCULATIONAHA.117.030012","article-title":"Sodium Glucose Cotransporter-2 Inhibition in Heart Failure: Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials","volume":"136","author":"Lytvyn","year":"2017","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1002\/phar.2527","article-title":"Impact of SGLT2 Inhibitors on Cardiovascular Outcomes in Patients with Heart Failure with Reduced Ejection Fraction","volume":"41","author":"Starr","year":"2021","journal-title":"Pharmacotherapy"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1007\/s12325-018-0708-y","article-title":"Effects of the SGLT-2 Inhibitor Empagliflozin on Renal Tissue Oxygenation in Non-Diabetic Subjects: A Randomized, Double-Blind, Placebo-Controlled Study Protocol","volume":"35","author":"Muller","year":"2018","journal-title":"Adv. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lymperopoulos, A., Borges, J.I., Cora, N., and Sizova, A. (2021). Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin\u2019s Effects in the Adrenal Gland. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147684"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2814","DOI":"10.1111\/dom.14517","article-title":"Effects of Empagliflozin on Erythropoiesis in Patients with Type 2 Diabetes: Data from a Randomized, Placebo-Controlled Study","volume":"23","author":"Thiele","year":"2021","journal-title":"Diabetes Obes. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"637","DOI":"10.21037\/cdt-20-585","article-title":"Actionable Secondary Findings in Arrhythmogenic Right Ventricle Cardiomyopathy Genes: Impact and Challenge of Genetic Counseling","volume":"11","author":"Abicht","year":"2021","journal-title":"Cardiovasc. Diagn. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Xing, L., Xue, Y., Yang, Y., Wu, P., Wong, C.C.L., Wang, H., Song, Z., Shi, D., Tong, C., and Yao, C. (2020). TMT-Based Quantitative Proteomic Analysis Identification of Integrin Alpha 3 and Integrin Alpha 5 as Novel Biomarkers in Pathogenesis of Acute Aortic Dissection. BioMed Res. Int., 2020.","DOI":"10.1155\/2020\/1068402"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12967-022-03842-5","article-title":"Angiotensin-(1-7) Ameliorates Sepsis-Induced Cardiomyopathy by Alleviating Inflammatory Response and Mitochondrial Damage through the NF-\u03baB and MAPK Pathways","volume":"21","author":"Chen","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.redox.2017.06.009","article-title":"The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats","volume":"13","author":"Steven","year":"2017","journal-title":"Redox Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1007\/s00018-021-04125-w","article-title":"Circulating Cardiomyocyte-Derived Extracellular Vesicles Reflect Cardiac Injury during Systemic Inflammatory Response Syndrome in Mice","volume":"79","author":"Hegyesi","year":"2022","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/s41392-022-01306-2","article-title":"CircRNA DICAR as a Novel Endogenous Regulator for Diabetic Cardiomyopathy and Diabetic Pyroptosis of Cardiomyocytes","volume":"8","author":"Yuan","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Yu, Y., Yang, H., Li, Q., Ding, N., Gao, J., Qiao, G., Feng, J., Zhang, X., Wu, J., and Yu, Y. (2023). Stress-Enhanced Cardiac lncRNA Morrbid Protects Hearts from Acute Myocardial Infarction. JCI Insight, 8.","DOI":"10.1172\/jci.insight.165568"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.yjmcc.2022.04.007","article-title":"Methods of Mouse Cardiomyocyte Isolation from Postnatal Heart","volume":"168","author":"Feng","year":"2022","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"eabe9716","DOI":"10.1126\/sciadv.abe9716","article-title":"Structural Insights into Integrin A5\u03b21 Opening by Fibronectin Ligand","volume":"7","author":"Schumacher","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Pacesa, M., Nickel, L., Schellhaas, C., Schmidt, J., Pyatova, E., Kissling, L., Barendse, P., Choudhury, J., Kapoor, S., and Alcaraz-Serna, A. (2025). One-Shot Design of Functional Protein Binders with BindCraft. Nature.","DOI":"10.1038\/s41586-025-09429-6"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Passaro, S., Corso, G., Wohlwend, J., Reveiz, M., Thaler, S., Somnath, V.R., Getz, N., Portnoi, T., Roy, J., and Stark, H. (2025). Boltz-2: Towards Accurate and Efficient Binding Affinity Prediction. bioRxiv.","DOI":"10.1101\/2025.06.14.659707"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e4792","DOI":"10.1002\/pro.4792","article-title":"UCSF ChimeraX: Tools for Structure Building and Analysis","volume":"32","author":"Meng","year":"2023","journal-title":"Protein Sci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/18\/1452\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:46:36Z","timestamp":1760035596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/18\/1452"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,16]]},"references-count":22,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["cells14181452"],"URL":"https:\/\/doi.org\/10.3390\/cells14181452","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,16]]}}}