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Miglustat, a glucosylceramide synthase EC 2.4.1.80 (GCS) inhibitor, is one of the few available pharmacological treatments; however, it is associated with significant adverse effects that impact patients\u2019 quality of life. Drug repurposing offers a promising strategy to identify new therapeutic agents from approved drugs, expanding treatment options for rare diseases with limited therapeutic alternatives. This study aims to identify potential alternative inhibitors of GCS through a drug-repurposing approach, using computational and experimental methods to assess their therapeutic potential for sphingolipidoses. A library of approved drugs was screened using advanced computational techniques, including molecular docking, molecular dynamics simulations, and metadynamics, to identify potential GCS inhibitors. Promising candidates were selected for further in vitro validation to evaluate their inhibitory activity and potential as therapeutic alternatives to Miglustat. Computational screening identified several potential GCS inhibitors, with Dapagliflozin emerging as the most promising candidate. Experimental validation confirmed its efficacy, revealing a complementary mechanism of action to Miglustat while potentially offering a more favorable side effect profile. This study underscores the utility of computational and experimental methodologies in drug repurposing for rare diseases. The identification of Dapagliflozin as a potential GCS inhibitor provides a foundation for further preclinical and clinical evaluation, supporting its potential application in the treatment of sphingolipidoses.<\/jats:p>","DOI":"10.3390\/ijms26052195","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T10:12:33Z","timestamp":1740737553000},"page":"2195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Targeting Glucosylceramide Synthase: Innovative Drug Repurposing Strategies for Lysosomal Diseases"],"prefix":"10.3390","volume":"26","author":[{"given":"Giorgia","family":"Canini","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Universit\u00e0 Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2508-0786","authenticated-orcid":false,"given":"Elena","family":"Mazzinelli","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Universit\u00e0 Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2799-4557","authenticated-orcid":false,"given":"Giuseppina","family":"Nocca","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Universit\u00e0 Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario \u201cA. 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Open Biol., 12.","DOI":"10.1098\/rsob.220155"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1750-1172-5-16","article-title":"Niemann-Pick Disease Type C","volume":"5","author":"Vanier","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_5","first-page":"1","article-title":"Lysosomal Storage Diseases","volume":"2","author":"Ferreira","year":"2017","journal-title":"Transl. Sci. Rare Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"jcs221739","DOI":"10.1242\/jcs.221739","article-title":"Lysosomal Storage Disorders\u2014Challenges, Concepts and Avenues for Therapy: Beyond Rare Diseases","volume":"132","author":"Marques","year":"2019","journal-title":"J. Cell Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1146\/annurev-med-122313-085916","article-title":"Lysosomal Storage Diseases: From Pathophysiology to Therapy","volume":"66","author":"Parenti","year":"2015","journal-title":"Annu. Rev. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/nrm2217","article-title":"Lysosomes: Fusion and Function","volume":"8","author":"Luzio","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.ymgme.2012.03.012","article-title":"Recommendations for the Diagnosis and Management of Niemann-Pick Disease Type C: An Update","volume":"106","author":"Patterson","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.ymgme.2016.12.003","article-title":"Differences in Niemann-Pick Disease Type C Symptomatology Observed in Patients of Different Ages","volume":"120","author":"Mengel","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1186\/1750-1172-8-166","article-title":"Niemann-Pick Disease Type C Symptomatology: An Expert-Based Clinical Description","volume":"8","author":"Mengel","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1023\/A:1012496514170","article-title":"Gaucher Disease: Understanding the Molecular Pathogenesis of Sphingolipidoses","volume":"24","author":"Cox","year":"2001","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.bbalip.2013.11.004","article-title":"Gaucher Disease and Fabry Disease: New Markers and Insights in Pathophysiology for Two Distinct Glycosphingolipidoses","volume":"1841","author":"Ferraz","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S143","DOI":"10.1016\/S1353-8020(13)70034-8","article-title":"Niemann-Pick\u2019s and Gaucher\u2019s Diseases","volume":"20","author":"Stern","year":"2014","journal-title":"Park. Relat. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/S0140-6736(01)05490-3","article-title":"Gaucher\u2019s Disease","volume":"358","author":"Elstein","year":"2001","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12944-021-01466-0","article-title":"Sphingolipid Lysosomal Storage Diseases: From Bench to Bedside","volume":"20","author":"Khodour","year":"2021","journal-title":"Lipids Health Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"s10","DOI":"10.1590\/1806-9282.66.s1.10","article-title":"Fabry Disease: Genetics, Pathology, and Treatment","volume":"66","author":"Bernardes","year":"2020","journal-title":"Rev. Assoc. Med. Bras."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.jbior.2018.08.001","article-title":"Niemann-Pick Type C Disease: The Atypical Sphingolipidosis","volume":"70","author":"Newton","year":"2018","journal-title":"Adv. Biol. Regul."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/j.ymthe.2017.03.025","article-title":"Hematopoietic Stem Cell Gene Therapy for Storage Disease: Current and New Indications","volume":"25","author":"Biffi","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_20","unstructured":"Kim, S.U. (2014). Lysosomal Storage Diseases: Stem Cell-Based Cell- and Gene-Therapy. Cell Transplant., epub ahead of print."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Shaimardanova, A.A., Chulpanova, D.S., Mullagulova, A.I., Afawi, Z., Gamirova, R.G., Solovyeva, V.V., and Rizvanov, A.A. (2022). Gene and Cell Therapy for Epilepsy: A Mini Review. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.868531"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1016\/B978-0-444-59565-2.00055-1","article-title":"Enzyme Replacement Therapy and Substrate Reduction Therapy in Lysosomal Storage Disorders with Neurological Expression","volume":"Volume 113","author":"Valayannopoulos","year":"2013","journal-title":"Handbook of Clinical Neurology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1038\/s41436-021-01156-3","article-title":"One-Year Results of a Clinical Trial of Olipudase Alfa Enzyme Replacement Therapy in Pediatric Patients with Acid Sphingomyelinase Deficiency","volume":"23","author":"Diaz","year":"2021","journal-title":"Genet. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1016\/j.ymthe.2019.05.018","article-title":"Substrate Reduction Therapy for Sandhoff Disease through Inhibition of Glucosylceramide Synthase Activity","volume":"27","author":"Marshall","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hughes, D.A., Deegan, P., Giraldo, P., G\u00f6ker-Alpan, \u00d6., Lau, H., Lukina, E., Revel-Vilk, S., Scarpa, M., Botha, J., and Gadir, N. (2022). Switching between Enzyme Replacement Therapies and Substrate Reduction Therapies in Patients with Gaucher Disease: Data from the Gaucher Outcome Survey (GOS). J. Clin. Med., 11.","DOI":"10.3390\/jcm11175158"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Coutinho, M., Santos, J., and Alves, S. (2016). Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17071065"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Weidemann, F., Jovanovic, A., Herrmann, K., and Vardarli, I. (2022). Chaperone Therapy in Fabry Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031887"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s12035-013-8605-5","article-title":"Chaperone Therapy for GM2 Gangliosidosis: Effects of Pyrimethamine on \u03b2-Hexosaminidase Activity in Sandhoff Fibroblasts","volume":"50","author":"Chiricozzi","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s00018-008-7470-2","article-title":"Chemical Chaperone Therapy for GM1-Gangliosidosis","volume":"65","author":"Suzuki","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Shaimardanova, A.A., Solovyeva, V.V., Issa, S.S., and Rizvanov, A.A. (2023). Gene Therapy of Sphingolipid Metabolic Disorders. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043627"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Issa, S.S., Shaimardanova, A.A., Valiullin, V.V., Rizvanov, A.A., and Solovyeva, V.V. (2022). Mesenchymal Stem Cell-Based Therapy for Lysosomal Storage Diseases and Other Neurodegenerative Disorders. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.859516"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"586","DOI":"10.4103\/1673-5374.266908","article-title":"Extracellular Vesicles in the Diagnosis and Treatment of Central Nervous System Diseases","volume":"15","author":"Shaimardanova","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/bs.pmbts.2024.03.034","article-title":"Drug Repurposing for Rare Diseases","volume":"207","author":"Israr","year":"2024","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jonker, A.H., O\u2019Connor, D., Cavaller-Bellaubi, M., Fetro, C., Gogou, M., \u2019t Hoen, P.A.C., de Kort, M., Stone, H., Valentine, N., and Pasmooij, A.M.G. (2024). Drug Repurposing for Rare: Progress and Opportunities for the Rare Disease Community. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1352803"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.tips.2021.01.003","article-title":"Drug Repurposing for Rare Diseases","volume":"42","author":"Roessler","year":"2021","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_36","unstructured":"Hughes, D.A., and Pastores, G.M. (1993). Gaucher Disease. GeneReviews\u00ae [Internet], University of Washington."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Stirnemann, J., Belmatoug, N., Camou, F., Serratrice, C., Froissart, R., Caillaud, C., Levade, T., Astudillo, L., Serratrice, J., and Brassier, A. (2017). A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020441"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s13023-018-0844-0","article-title":"Miglustat in Niemann-Pick Disease Type C Patients: A Review","volume":"13","author":"Pineda","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1007\/s11011-021-00842-0","article-title":"Treatment Trials in Niemann-Pick Type C Disease","volume":"36","author":"Sitarska","year":"2021","journal-title":"Metab. Brain Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8755","DOI":"10.1021\/acsomega.2c08219","article-title":"Human Glucosylceramide Synthase at Work as Provided by \u201cIn Silico\u201d Molecular Docking, Molecular Dynamics, and Metadynamics","volume":"8","author":"Canini","year":"2023","journal-title":"ACS Omega"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1021\/acs.jcim.5b00559","article-title":"ZINC 15\u2014Ligand Discovery for Everyone","volume":"55","author":"Sterling","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1021\/jm030644s","article-title":"Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening","volume":"47","author":"Halgren","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein\u2212Ligand Complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Dasmahapatra, U., Kumar, C.K., Das, S., Subramanian, P.T., Murali, P., Isaac, A.E., Ramanathan, K., Mm, B., and Chanda, K. (2022). In-Silico Molecular Modelling, MM\/GBSA Binding Free Energy and Molecular Dynamics Simulation Study of Novel Pyrido Fused Imidazo[4,5-c]Quinolines as Potential Anti-Tumor Agents. Front. Chem., 10.","DOI":"10.3389\/fchem.2022.991369"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA Methods to Estimate Ligand-Binding Affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/0003-9861(90)90657-K","article-title":"Glucosylceramide Synthase of Mouse Kidney: Further Characterization with an Improved Assay Method","volume":"283","author":"Shukla","year":"1990","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5802","DOI":"10.1016\/S0021-9258(18)91935-6","article-title":"Enzymatic Synthesis of Ceramide-Glucose and Ceramide-Lactose by Glycosyltransferases from Embryonic Chicken Brain","volume":"243","author":"Basu","year":"1968","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"26492","DOI":"10.1074\/jbc.M102612200","article-title":"Identification of Active Site Residues in Glucosylceramide Synthase","volume":"276","author":"Marks","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"877","DOI":"10.2147\/TCRM.S5777","article-title":"New Therapies in the Management of Niemann-Pick Type C Disease: Clinical Utility of Miglustat","volume":"5","author":"Wraith","year":"2009","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0957-4166(99)00468-1","article-title":"Molecular Requirements of Imino Sugars for the Selective Control of N-Linked Glycosylation and Glycosphingolipid Biosynthesis","volume":"11","author":"Butters","year":"2000","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"D668","DOI":"10.1093\/nar\/gkj067","article-title":"DrugBank: A Comprehensive Resource for in Silico Drug Discovery and Exploration","volume":"34","author":"Wishart","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1042\/bj3410395","article-title":"Histidine-193 of Rat Glucosylceramide Synthase Resides in a UDP-Glucose- and Inhibitor (D-Threo-1-Phenyl-2-Decanoylamino-3-Morpholinopropan-1-Ol)-Binding Region: A Biochemical and Mutational Study","volume":"341","author":"Wu","year":"1999","journal-title":"Biochem. J."},{"key":"ref_54","unstructured":"Padda, I.S., Mahtani, A.U., and Parmar, M. (2023). Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors. StatPearls [Internet], StatPearls Publishing."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1111\/dom.12418","article-title":"Pharmacodynamic Differences between Canagliflozin and Dapagliflozin: Results of a Randomized, Double-Blind, Crossover Study","volume":"17","author":"Sha","year":"2015","journal-title":"Diabetes Obes. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"34213","DOI":"10.1074\/jbc.M906368199","article-title":"Cellular Gangliosides Promote Growth Factor-Induced Proliferation of Fibroblasts","volume":"275","author":"Li","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1021\/jm050540c","article-title":"Novel Procedure for Modeling Ligand\/Receptor Induced Fit Effects","volume":"49","author":"Sherman","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0022-2836(02)00470-9","article-title":"On the Role of the Crystal Environment in Determining Protein Side-Chain Conformations","volume":"320","author":"Jacobson","year":"2002","journal-title":"J. Mol. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"11673","DOI":"10.1021\/jp021564n","article-title":"Force Field Validation Using Protein Side Chain Prediction","volume":"106","author":"Jacobson","year":"2002","journal-title":"J. Phys. Chem. B"},{"key":"ref_60","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_61","doi-asserted-by":"crossref","first-page":"D1373","DOI":"10.1093\/nar\/gkac956","article-title":"PubChem 2023 Update","volume":"51","author":"Kim","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1021\/acs.jctc.5b00864","article-title":"OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins","volume":"12","author":"Harder","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High Performance Molecular Simulations through Multi-Level Parallelism from Laptops to Supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nmeth.4067","article-title":"CHARMM36m: An Improved Force Field for Folded and Intrinsically Disordered Proteins","volume":"14","author":"Huang","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1021\/acs.jctc.8b00839","article-title":"Cation-\u03c0 Interactions between Methylated Ammonium Groups and Tryptophan in the CHARMM36 Additive Force Field","volume":"15","author":"Khan","year":"2019","journal-title":"J. Chem. Theory Comput."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/jcc.21287","article-title":"CHARMM: The Biomolecular Simulation Program","volume":"30","author":"Brooks","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1002\/jbm.820261004","article-title":"In Vitro Synergistic, Antagonistic, and Duration of Exposure Effects of Metal Cations on Eukaryotic Cells","volume":"26","author":"Wataha","year":"1992","journal-title":"J. Biomed. Mater. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2195\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:44:47Z","timestamp":1760028287000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,28]]},"references-count":67,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26052195"],"URL":"https:\/\/doi.org\/10.3390\/ijms26052195","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,28]]}}}