{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:18:05Z","timestamp":1788499085436,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001843","name":"SERB-Power","doi-asserted-by":"publisher","award":["SPG\/2021\/002833"],"award-info":[{"award-number":["SPG\/2021\/002833"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Biotechnology","award":["BT\/PR63605\/MRNAR\/169\/22\/2025"],"award-info":[{"award-number":["BT\/PR63605\/MRNAR\/169\/22\/2025"]}]},{"award":["BT\/PR63605\/MRNAR\/169\/22\/2025"],"award-info":[{"award-number":["BT\/PR63605\/MRNAR\/169\/22\/2025"]}],"id":[{"id":"https:\/\/ror.org\/03tjsyq23","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Temozolomide (TMZ) resistance remains a fundamental obstacle in the treatment of glioblastoma (GBM). While the metabolic sensor AMPK is known to influence cancer cell survival, the specific role of its regulatory \u03b3-subunit isoforms in orchestrating chemoresistance is poorly understood. This study investigates how the dynamic remodeling of the AMPK heterotrimer contributes to TMZ evasion in GBM. We observed significantly low expression of AMPK\u03b32 in glioma patient samples, but the treatment of GBM cell lines with TMZ led to a robust increase in AMPK\u03b32 expression with a concomitant decrease in AMPK\u03b31 expression. We identified a significant \u201cisoform switch\u201d in TMZ-treated cells, characterized by a marked downregulation of the \u03b31 subunit and a reciprocal upregulation of \u03b32. The structural remodeling of the AMPK complex was validated using co-immunoprecipitation (Co-IP). Co-IP analysis confirmed that the AMPK \u03b1 catalytic subunit shifts its primary association from \u03b31 to \u03b32 during the TMZ treatment. Functionally, \u03b32-dominant complexes exhibited reduced sensitivity to ATP-mediated inhibition, allowing resistant cells to maintain better ATP homeostasis and sustained AMPK activation under TMZ-induced stress. Furthermore, the knockdown of the \u03b32 subunit abolished this metabolic advantage, resulting in the resensitization of GBM cell lines to TMZ-induced cell death. Our findings reveal that AMPK \u03b3-subunit isoform switching is a previously unrecognized metabolic adaptation that drives TMZ resistance in GBM. Targeting the \u03b32-specific complex or preventing this isoform transition represents a promising therapeutic strategy to overcome chemoresistance in malignant gliomas.<\/jats:p>","DOI":"10.3390\/cells15171594","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:02:52Z","timestamp":1788343372000},"page":"1594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AMPK \u03b3-Subunit Isoform Switching Governs Temozolomide Resistance and Survival in Glioblastoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5127-3550","authenticated-orcid":false,"given":"Shweta","family":"Dongre","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Central University of Rajasthan, Ajmer 305817, India"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Arpit","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Central University of Rajasthan, Ajmer 305817, India"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Naveen","family":"Soni","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Central University of Rajasthan, Ajmer 305817, India"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Bhawana","family":"Bissa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Central University of Rajasthan, Ajmer 305817, India"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2759","DOI":"10.1038\/s44318-024-00120-6","article-title":"Energy Stress Promotes P-Bodies Formation via Lysine-63-Linked Polyubiquitination of HAX1","volume":"43","author":"Zhan","year":"2024","journal-title":"EMBO J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1016\/j.molcel.2021.08.015","article-title":"AMPK: Restoring Metabolic Homeostasis over Space and Time","volume":"81","author":"Trefts","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"113614","DOI":"10.1016\/j.yexcr.2023.113614","article-title":"AMP-Activated Protein Kinase: An Energy Sensor and Survival Mechanism in the Reinstatement of Metabolic Homeostasis","volume":"428","author":"Sharma","year":"2023","journal-title":"Exp. Cell Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.cmet.2023.03.019","article-title":"Nutrient-Sensing AgRP Neurons Relay Control of Liver Autophagy during Energy Deprivation","volume":"35","author":"Chen","year":"2023","journal-title":"Cell Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/d41573-021-00021-x","article-title":"A New Route to Regulating AMPK Activity","volume":"20","author":"Crunkhorn","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1111\/febs.13698","article-title":"AMP-Activated Protein Kinase: A Cellular Energy Sensor That Comes in 12 Flavours","volume":"283","author":"Ross","year":"2016","journal-title":"FEBS J."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Rakoubian, A., Khinchin, J., Yarbro, J., Kobayashi, S., and Liang, Q. (2025). Isoform-Specific Roles of AMP-Activated Protein Kinase in Cardiac Physiology and Pathophysiology. Front. Cardiovasc. Med., 12.","DOI":"10.3389\/fcvm.2025.1638515"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wang, S., Li, H., Yuan, M., Fan, H., and Cai, Z. (2022). Role of AMPK in Autophagy. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.1015500"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.semcancer.2024.08.002","article-title":"AMPK: The Energy Sensor at the Crossroads of Aging and Cancer","volume":"106","author":"Penugurti","year":"2024","journal-title":"Semin. Cancer Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1042\/BCJ20170458","article-title":"Phosphorylation of AMPK by Upstream Kinases Is Required for Activity in Mammalian Cells","volume":"474","author":"Willows","year":"2017","journal-title":"Biochem. J."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Taylor, O.G., Brzozowski, J.S., and Skelding, K.A. (2019). Glioblastoma Multiforme: An Overview of Emerging Therapeutic Targets. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.00963"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"105780","DOI":"10.1016\/j.phrs.2021.105780","article-title":"Glioblastoma Multiforme (GBM): An Overview of Current Therapies and Mechanisms of Resistance","volume":"171","author":"Wu","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kr\u00f3likowska, K., B\u0142aszczak, K., \u0141awicki, S., Zajkowska, M., and Gudowska-Sawczuk, M. (2025). Glioblastoma\u2014A Contemporary Overview of Epidemiology, Classification, Pathogenesis, Diagnosis, and Treatment: A Review Article. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262412162"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kordyukova, M.Y., Bulgakov, T.K., Sorokina, M.A., Kudryashova, O.M., Abakumova, T.O., Meshcheryakova, V.I., Grigoriev, I.V., Senko, I.V., Shevchenko, E.K., and Belousov, V.V. (2026). Overcoming Chemoresistance in Glioblastoma: Mechanisms, Therapeutic Strategies, and Functional Precision Medicine. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27052207"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104820","DOI":"10.1016\/j.critrevonc.2025.104820","article-title":"Autophagy and Oxidative Stress in Solid Tumors: Mechanisms and Therapeutic Opportunities","volume":"212","year":"2025","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1038\/ncb2329","article-title":"The AMP-Activated Protein Kinase (AMPK) Signaling Pathway Coordinates Cell Growth, Autophagy, & Metabolism","volume":"13","author":"Mihaylova","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/s41420-024-02011-5","article-title":"AMPK-a Key Factor in Crosstalk between Tumor Cell Energy Metabolism and Immune Microenvironment?","volume":"10","author":"Wang","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Keerthana, C.K., Rayginia, T.P., Shifana, S.C., Anto, N.P., Kalimuthu, K., Isakov, N., and Anto, R.J. (2023). The Role of AMPK in Cancer Metabolism and Its Impact on the Immunomodulation of the Tumor Microenvironment. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1114582"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s13046-025-03346-2","article-title":"AMP-Activated Protein Kinase Mediates Adaptation of Glioblastoma Cells to Conditions of the Tumor Microenvironment","volume":"44","author":"Lorenz","year":"2025","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"188785","DOI":"10.1016\/j.bbcan.2022.188785","article-title":"AMPK: An Odyssey of a Metabolic Regulator, a Tumor Suppressor, and Now a Contextual Oncogene","volume":"1877","author":"Penugurti","year":"2022","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.molcel.2017.05.032","article-title":"AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance","volume":"66","author":"Garcia","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1042\/BCJ20170046","article-title":"Effect of Different \u03b3-Subunit Isoforms on the Regulation of AMPK","volume":"474","author":"Willows","year":"2017","journal-title":"Biochem. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3856","DOI":"10.1038\/s41467-022-31190-x","article-title":"Spatial Regulation of AMPK Signaling Revealed by a Sensitive Kinase Activity Reporter","volume":"13","author":"Schmitt","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"W98","DOI":"10.1093\/nar\/gkx247","article-title":"GEPIA: A Web Server for Cancer and Normal Gene Expression Profiling and Interactive Analyses","volume":"45","author":"Tang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/pro.3307","article-title":"The Human Protein Atlas: A Spatial Map of the Human Proteome","volume":"27","author":"Thul","year":"2018","journal-title":"Protein Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"D1202","DOI":"10.1093\/nar\/gkv951","article-title":"PubChem Substance and Compound Databases","volume":"44","author":"Kim","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An Open Chemical Toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kemmish, H., Fasnacht, M., and Yan, L. (2017). Fully Automated Antibody Structure Prediction Using BIOVIA Tools: Validation Study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0177923"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/bmb.20966","article-title":"Using the PyMOL Application to Reinforce Visual Understanding of Protein Structure","volume":"44","author":"Rigsby","year":"2016","journal-title":"Biochem. Mol. Biol. Educ."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/bib\/2.2.195","article-title":"Swiss-PDB Viewer (Deep View)","volume":"2","author":"Kaplan","year":"2001","journal-title":"Brief. Bioinform."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/978-1-4939-6952-4_20","article-title":"AutoDock and AutoDockTools for Protein-Ligand Docking: Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1(BACE1) as a Case Study","volume":"1598","author":"Khalil","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/s41401-019-0228-6","article-title":"CB-Dock: A Web Server for Cavity Detection-Guided Protein-Ligand Blind Docking","volume":"41","author":"Liu","year":"2020","journal-title":"Acta. Pharmacol. Sin."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_35","first-page":"262","article-title":"An extension strategy of Discovery Studio 2.0 for non-bonded interaction energy automatic calculation at the residue level","volume":"32","author":"Gao","year":"2011","journal-title":"Zool. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/neuonc\/now247","article-title":"GlioVis Data Portal for Visualization and Analysis of Brain Tumor Expression Datasets","volume":"19","author":"Bowman","year":"2017","journal-title":"Neuro-Oncology"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Liang, M., Li, J.W., Luo, H., Lulu, S., Calbay, O., Shenoy, A., Tan, M., Law, B.K., Huang, S., and Xiao, T.S. (2022). Epithelial\u2013Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress. Cells, 11.","DOI":"10.3390\/cells11142208"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3892\/mmr.2014.2151","article-title":"Temozolomide Induces Autophagy via ATM-AMPK-ULK1 Pathways in Glioma","volume":"10","author":"Zou","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"40461","DOI":"10.1074\/jbc.M110.164046","article-title":"Activation of AMP-Activated Protein Kinase by Temozolomide Contributes to Apoptosis in Glioblastoma Cells via P53 Activation and mTORC1 Inhibition","volume":"285","author":"Zhang","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Bonam, S.R., Bayry, J., Tschan, M.P., and Muller, S. (2020). Progress and Challenges in the Use of MAP1LC3 as a Legitimate Marker for Measuring Dynamic Autophagy In Vivo. Cells, 9.","DOI":"10.3390\/cells9051321"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"102421","DOI":"10.1016\/j.redox.2022.102421","article-title":"Phospholipid Peroxidation Inhibits Autophagy via Stimulating the Delipidation of Oxidized LC3-PE","volume":"55","author":"Li","year":"2022","journal-title":"Redox Biol."},{"key":"ref_42","unstructured":"(2026, July 22). Selective Autophagy Receptor P62\/SQSTM1, a Pivotal Player in Stress and Aging-PMC, Available online: https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC8883344\/."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2020.1797280","article-title":"Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy (4th Edition)1","volume":"17","author":"Klionsky","year":"2021","journal-title":"Autophagy"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"102068","DOI":"10.1016\/j.mcp.2026.102068","article-title":"Metformin and Oncogenic Pathways: Crosstalk between Energy Sensing and Tumor Progression","volume":"86","author":"Zhang","year":"2026","journal-title":"Mol. Cell. Probes"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Yalamarty, S.S.K., Filipczak, N., Li, X., Subhan, M.A., Parveen, F., Ataide, J.A., Rajmalani, B.A., and Torchilin, V.P. (2023). Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM). Cancers, 15.","DOI":"10.3390\/cancers15072116"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Esparza-Salazar, F., Murguiondo-P\u00e9rez, R., Cano-Herrera, G., Bautista-Gonzalez, M.F., Loza-L\u00f3pez, E.C., M\u00e9ndez-Vionet, A., Van-Tienhoven, X.A., Chumaceiro-Natera, A., Simental-Aldaba, E., and Ibarra, A. (2025). Glioblastoma: A Multidisciplinary Approach to Its Pathophysiology, Treatment, and Innovative Therapeutic Strategies. Biomedicines, 13.","DOI":"10.3390\/biomedicines13081882"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1111\/joim.12268","article-title":"AMP-Activated Protein Kinase: A Key Regulator of Energy Balance with Many Roles in Human Disease","volume":"276","year":"2014","journal-title":"J. Intern. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"105488","DOI":"10.1016\/j.jbc.2023.105488","article-title":"Overexpression of AMPK\u03b32 Increases AMPK Signaling to Augment Human T Cell Metabolism and Function","volume":"300","author":"Braverman","year":"2023","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Afinanisa, Q., Cho, M.K., and Seong, H.-A. (2021). AMPK Localization: A Key to Differential Energy Regulation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222010921"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1080\/10409238.2020.1727840","article-title":"Spatial Control of AMPK Signaling at Subcellular Compartments","volume":"55","author":"Chauhan","year":"2020","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_51","first-page":"197","article-title":"AMP-Activated Protein Kinase and Energy Balance in Breast Cancer","volume":"9","author":"Zhao","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1161\/CIRCRESAHA.117.311159","article-title":"Activation of \u03932-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia\/Reperfusion Injury","volume":"121","author":"Cao","year":"2017","journal-title":"Circ. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10482","DOI":"10.1038\/s41598-020-67030-5","article-title":"The Importance of the AMPK Gamma 1 Subunit in Metformin Suppression of Liver Glucose Production","volume":"10","author":"An","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"H283","DOI":"10.1152\/ajpheart.00813.2016","article-title":"A Novel, de Novo Mutation in the PRKAG2 Gene: Infantile-Onset Phenotype and the Signaling Pathway Involved","volume":"313","author":"Xu","year":"2017","journal-title":"Am. J. Physiol. Heart Circ. Physiol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/17\/1594\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:40:44Z","timestamp":1788496844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/17\/1594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,2]]},"references-count":54,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cells15171594"],"URL":"https:\/\/doi.org\/10.3390\/cells15171594","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,2]]}}}