{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T12:55:03Z","timestamp":1790600103881,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["10.55776\/COE14"],"award-info":[{"award-number":["10.55776\/COE14"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["10.55776\/W1226"],"award-info":[{"award-number":["10.55776\/W1226"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"award":["10.55776\/COE14"],"award-info":[{"award-number":["10.55776\/COE14"]}],"id":[{"id":"https:\/\/ror.org\/013tf3c58","id-type":"ROR","asserted-by":"publisher"}]},{"award":["10.55776\/W1226"],"award-info":[{"award-number":["10.55776\/W1226"]}],"id":[{"id":"https:\/\/ror.org\/013tf3c58","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: For appropriate glucose sensing, pancreatic beta-cells essentially establish a constant mitochondria-directed endoplasmic reticulum (ER) Ca2+ leak via phosphorylated presenilin-1 (PS1). In the current work, we investigated how cells maintain the ER Ca2+ content during this continuous Ca2+ leak. Methods: Ca2+ imaging for ER, cytosolic and subplasmalemmal Ca2+, high resolution respirometry, and ELISA for insulin secretion were used. Results: A novel ER Ca2+ refilling mechanism driven by reverse-mode NCX2, which is fueled by local Na+ influxes through TRPC3 and TRPV4 channels that are independent of STIM-ORAI1 was found in pancreatic rodent and human beta cell lines. Disrupting this TRPs-NCX2 axis reduces subplasmalemmal Ca2+ levels, abolishes glucose-induced cytosolic Ca2+ oscillations, suppresses glucose-triggered elevation in mitochondrial energetics, and impairs first-phase insulin secretion. Conclusions: We identified a novel, ORAI1-independent \u201cTRPs-NCX2\u201d relay that couples Na+ influx via TRPC3 and TRPV4 to NCX2 reverse mode to maintain ER Ca2+ stores during physiological basal ER Ca2+ leakage, which is fundamental to beta-cell responsiveness to elevated glucose.<\/jats:p>","DOI":"10.3390\/cells15191766","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:35:59Z","timestamp":1790595359000},"page":"1766","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TRPs\u2014NCX2 Axis Jointly Preserves Pancreatic Beta Cell Susceptibility\/Sensitivity to Elevated Glucose"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8444-4409","authenticated-orcid":false,"given":"Adlet","family":"Sagintayev","sequence":"first","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6\/4east, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1130-8970","authenticated-orcid":false,"given":"Furkan E.","family":"Oflaz","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6\/4east, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Andra","family":"Kanlinuro","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6\/4east, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2611-5053","authenticated-orcid":false,"given":"Savina","family":"van Amsterdam","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6\/4east, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5588-7698","authenticated-orcid":false,"given":"Benjamin","family":"Gottschalk","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6\/4east, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Rene","family":"Rost","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6\/4east, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Zhanat","family":"Koshenov","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6\/4east, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6327-8729","authenticated-orcid":false,"given":"Roland","family":"Malli","sequence":"additional","affiliation":[{"name":"Core Facility Bioimaging, Center for Medical Research (ZMF), Medical University of Graz, 8010 Graz, Austria"},{"name":"BioTechMed-Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1871-3298","authenticated-orcid":false,"given":"Wolfgang F.","family":"Graier","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6\/4east, 8010 Graz, Austria"},{"name":"BioTechMed-Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Klec, C., Ziomek, G., Pichler, M., Malli, R., and Graier, W.F. (2019). Calcium Signaling in \u03b2-Cell Physiology and Pathology: A Revisit. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246110"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.33594\/000000005","article-title":"Glycogen Synthase Kinase 3 Beta Controls Presenilin-1-Mediated Endoplasmic Reticulum Ca2+ Leak Directed to Mitochondria in Pancreatic Islets and \u03b2-Cells","volume":"52","author":"Klec","year":"2019","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"573","DOI":"10.33594\/000000158","article-title":"Presenilin-1 Established ER-Ca2+ Leak: A Follow up on Its Importance for the Initial Insulin Secretion in Pancreatic Islets and \u03b2-Cells Upon Elevated Glucose","volume":"53","author":"Klec","year":"2019","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"M2","DOI":"10.1007\/s00125-002-0930-6","article-title":"Loss of Early Insulin Secretion Leads to Postprandial Hyperglycaemia","volume":"46","author":"Prato","year":"2003","journal-title":"Diabetologia"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Koshenov, Z., Postic, S., Schoiswohl, G., van Amsterdam, S., Hois-Zelinka, V., Oflaz, F.E., Rost, R., Tiapko, O., Gottschalk, B., and Hirtl, M. (2026, September 25). Presenilin-1 Controls Glycolysis and Identity of Pancreatic Beta Cells. Commun. Biol., Available online: https:\/\/www.nature.com\/articles\/s42003-026-10581-6#citeas.","DOI":"10.1038\/s42003-026-10581-6"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ceca.2007.03.009","article-title":"Role of STIM and Orai Proteins in the Store-Operated Calcium Signaling Pathway","volume":"42","author":"Hewavitharana","year":"2007","journal-title":"Cell Calcium"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"20661","DOI":"10.1074\/jbc.C600126200","article-title":"Orai1 and STIM Reconstitute Store-Operated Calcium Channel Function","volume":"281","author":"Soboloff","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"ncb1435","DOI":"10.1038\/ncb1435","article-title":"Amplification of CRAC Current by STIM1 and CRACM1 (Orai1)","volume":"8","author":"Peinelt","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1083\/jcb.200604014","article-title":"Ca2+ Store Depletion Causes STIM1 to Accumulate in ER Regions Closely Associated with the Plasma Membrane","volume":"174","author":"Wu","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"pe42","DOI":"10.1126\/scisignal.3148pe42","article-title":"Calcium Signaling by STIM and Orai: Intimate Coupling Details Revealed","volume":"3","author":"Wang","year":"2010","journal-title":"Sci. Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4536","DOI":"10.1038\/s41467-018-06816-8","article-title":"Calcium Sensing by the STIM1 ER-Luminal Domain","volume":"9","author":"Gudlur","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1038\/s44318-025-00454-9","article-title":"Annexin A5 Controls VDAC1-Dependent Mitochondrial Ca2+ Homeostasis and Determines Cellular Susceptibility to Apoptosis","volume":"44","author":"Oflaz","year":"2025","journal-title":"EMBO J."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Oflaz, F.E., Koshenov, Z., Hirtl, M., Rost, R., Malli, R., and Graier, W.F. (2022). Sigma-1 Receptor Modulation by Ligands Coordinates Cancer Cell Energy Metabolism. Biomolecules, 12.","DOI":"10.3390\/biom12060762"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17404","DOI":"10.1073\/pnas.0408030101","article-title":"Bcl-2-Mediated Alterations in Endoplasmic Reticulum Ca2+ Analyzed with an Improved Genetically Encoded Fluorescent Sensor","volume":"101","author":"Palmer","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","first-page":"2944","article-title":"IP3-Mediated STIM1 Oligomerization Requires Intact Mitochondrial Ca2+ Uptake","volume":"127","author":"Deak","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"ncb2906","DOI":"10.1038\/ncb2906","article-title":"A Polarized Ca2+, Diacylglycerol and STIM1 Signalling System Regulates Directed Cell Migration","volume":"16","author":"Tsai","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1096\/fj.05-5397fje","article-title":"A Novel Pathway of Cell Growth Regulation Mediated by a PLA2\u03b1-Derived Phosphoinositide Metabolite","volume":"20","author":"Filippi","year":"2006","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"80278","DOI":"10.18632\/oncotarget.20571","article-title":"UCP2 and PRMT1 Are Key Prognostic Markers for Lung Carcinoma Patients","volume":"8","author":"Klec","year":"2017","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"34445","DOI":"10.1074\/jbc.M112.392084","article-title":"Mitochondrial Ca2+ Uptake 1 (MICU1) and Mitochondrial Ca2+ Uniporter (MCU) Contribute to Metabolism-Secretion Coupling in Clonal Pancreatic \u03b2-Cells","volume":"287","author":"Alam","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10923","DOI":"10.1074\/jbc.M112.414961","article-title":"Metabolome Response to Glucose in the \u03b2-Cell Line INS-1 832\/13*","volume":"288","author":"Lorenz","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.1242\/jcs.034496","article-title":"Cytosolic Ca2+ Prevents the Subplasmalemmal Clustering of STIM1: An Intrinsic Mechanism to Avoid Ca2+ Overload","volume":"121","author":"Malli","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1111\/j.1476-5381.2012.02126.x","article-title":"Novel Pyrazole Compounds for Pharmacological Discrimination between Receptor-operated and Store-operated Ca2+ Entry Pathways","volume":"167","author":"Schleifer","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"19084","DOI":"10.1073\/pnas.1005333107","article-title":"Inhibition of the Cation Channel TRPV4 Improves Bladder Function in Mice and Rats with Cyclophosphamide-Induced Cystitis","volume":"107","author":"Everaerts","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.ceca.2005.06.028","article-title":"TRP Channels: An Overview","volume":"38","author":"Pedersen","year":"2005","journal-title":"Cell Calcium"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1111\/j.1469-7793.2000.00701.x","article-title":"Histamine-induced Ca2+ Oscillations in a Human Endothelial Cell Line Depend on Transmembrane Ion Flux, Ryanodine Receptors and Endoplasmic Reticulum Ca2+-ATPase","volume":"524","author":"Frieden","year":"2000","journal-title":"J. Physiol."},{"key":"ref_26","first-page":"889","article-title":"Resting Membrane Potential Regulates Na+\u2013Ca2+ Exchange-Mediated Ca2+ Overload during Hypoxia\u2013Reoxygenation in Rat Ventricular Myocytes","volume":"550","author":"Giles","year":"2009","journal-title":"J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.cardiores.2006.10.016","article-title":"Phospholipase C-Dependent Control of Cardiac Calcium Homeostasis Involves a TRPC3-NCX1 Signaling Complex","volume":"73","author":"Eder","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1042\/bj2850435","article-title":"Regulation of Pyruvate Dehydrogenase by Insulin and Polyamines within Electropermeabilized Fat-Cells and Isolated Mitochondria","volume":"285","author":"Rutter","year":"1992","journal-title":"Biochem. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1042\/bj2180235","article-title":"Role of Ca2+ Ions in the Regulation of Intramitochondrial Metabolism in Rat Heart. Evidence from Studies with Isolated Mitochondria That Adrenaline Activates the Pyruvate Dehydrogenase and 2-Oxoglutarate Dehydrogenase Complexes by Increasing the Intramitochondrial Concentration of Ca2+","volume":"218","author":"McCormack","year":"1984","journal-title":"Biochem. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1016\/j.bbabio.2009.01.019","article-title":"Mitochondrial Calcium as a Key Regulator of Mitochondrial ATP Production in Mammalian Cells","volume":"1787","author":"Griffiths","year":"2009","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Bioenerg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/j.1749-6632.1989.tb14998.x","article-title":"The Role of Ca2+ in the Hormonal Regulation of the Activities of Pyruvate Dehydrogenase and Oxoglutarate Dehydrogenase Complexes","volume":"573","author":"Rutter","year":"1989","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10506","DOI":"10.1074\/jbc.L120.013975","article-title":"The Roles of Cytosolic and Intramitochondrial Ca2+ and the Mitochondrial Ca2+-Uniporter (MCU) in the Stimulation of Mammalian Oxidative Phosphorylation","volume":"295","author":"Rutter","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1113\/jphysiol.2005.102780","article-title":"TRPC3 Properties of a Native Constitutively Active Ca2+-permeable Cation Channel in Rabbit Ear Artery Myocytes","volume":"571","author":"Albert","year":"2006","journal-title":"J. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6827","DOI":"10.1113\/JP287092","article-title":"TRPV4 Couples with NCX1 to Mediate Glucose-dependent Glucagon-like Peptide-1 Release and Improve Glucose Homeostasis","volume":"602","author":"Chen","year":"2024","journal-title":"J. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"16711","DOI":"10.1038\/16711","article-title":"Direct Activation of Human TRPC6 and TRPC3 Channels by Diacylglycerol","volume":"397","author":"Hofmann","year":"1999","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"321","DOI":"10.3109\/03009738009179202","article-title":"Ca2+ Transport in Pancreatic \u03b2-Cells during Glucose Stimulation of Insulin Secretion","volume":"85","author":"Hellman","year":"2010","journal-title":"Upsala J. M\u00e9d. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zhang, J., Wei, Y., Bai, S., Ding, S., Gao, H., Yin, S., Chen, S., Lu, J., Wang, H., and Shen, Y. (2019). TRPV4 Complexes with the Na+\/Ca2+ Exchanger and IP3 Receptor 1 to Regulate Local Intracellular Calcium and Tracheal Tension in Mice. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01471"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2204846","DOI":"10.1002\/advs.202204846","article-title":"TRPC3 Regulates Islet Beta-Cell Insulin Secretion","volume":"10","author":"Rached","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1113\/jphysiol.1968.sp008433","article-title":"The Role of Sodium and Potassium in Insulin Secretion from Rabbit Pancreas","volume":"194","author":"Hales","year":"1968","journal-title":"J. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.cellsig.2017.03.018","article-title":"TRPV4 Regulates Insulin mRNA Expression and INS-1E Cell Death via ERK1\/2 and NO-Dependent Mechanisms","volume":"35","author":"Billert","year":"2017","journal-title":"Cell. Signal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1111\/jdi.13244","article-title":"Transient Receptor Potential Vanilloid 4 Channels as Therapeutic Targets in Diabetes and Diabetes-related Complications","volume":"11","author":"Hu","year":"2020","journal-title":"J. Diabetes Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1042\/BST20170505","article-title":"Control of Pancreatic \u03b2-Cell Bioenergetics","volume":"46","author":"Affourtit","year":"2018","journal-title":"Biochem. Soc. Trans."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Nieves, A.M.R., Wauford, B.M., and Fu, A. (2024). Mitochondrial Bioenergetics, Metabolism, and beyond in Pancreatic \u03b2-Cells and Diabetes. Front. Mol. Biosci., 11.","DOI":"10.3389\/fmolb.2024.1354199"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/s42003-022-03019-2","article-title":"Citrin Mediated Metabolic Rewiring in Response to Altered Basal Subcellular Ca2+ Homeostasis","volume":"5","author":"Koshenov","year":"2022","journal-title":"Commun. Biol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1766\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:55:27Z","timestamp":1790596527000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1766"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":44,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cells15191766"],"URL":"https:\/\/doi.org\/10.3390\/cells15191766","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]}}}