{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T14:02:41Z","timestamp":1777125761685,"version":"3.51.4"},"reference-count":56,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"national funds through Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P.","award":["UIDB\/04293\/2020"],"award-info":[{"award-number":["UIDB\/04293\/2020"]}]},{"name":"national funds through Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P.","award":["2022.02305.PTDC"],"award-info":[{"award-number":["2022.02305.PTDC"]}]},{"name":"national funds through Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P.","award":["CEECIND\/00724\/2017"],"award-info":[{"award-number":["CEECIND\/00724\/2017"]}]},{"name":"national funds through Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P.","award":["CEECIND\/00724\/2017\/CP1386\/CT0006"],"award-info":[{"award-number":["CEECIND\/00724\/2017\/CP1386\/CT0006"]}]},{"name":"the EMBO Scientific Exchange","award":["9890"],"award-info":[{"award-number":["9890"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The N88S mutation in human seipin causes a dominant motor neuron disease marked by ER stress and inclusion body formation, lipid imbalance, and oxidative damage. However, the metabolic mechanisms connecting these defects remain poorly understood. Previous proteomic profiling in our yeast model of N88S human seipinopathy revealed decreased protein levels of enzymes involved in the tricarboxylic acid cycle, fatty acid and carboxylic acid metabolism, and the glyoxylate cycle, suggesting impaired downstream utilization of peroxisome-derived acetyl-CoA. Guided by these findings, we investigated how peroxisomal function contributes to cellular dyshomeostasis. N88S seipin-expressing cells exhibited increased peroxisome abundance but defective routing of acetyl-CoA into mitochondrial and glyoxylate pathways, resulting in elevated reactive oxygen species (ROS), impaired glyoxylate cycle activation, and reduced metabolic adaptability to non-fermentable carbon sources. Loss of peroxisomes or forced cytosolic redirection of acetyl-CoA further exacerbated ER stress, ROS accumulation, lipid peroxidation, and the growth defect on N88S seipin-expressing cells, whereas inhibition of fatty acid synthesis mitigated oxidative damage. These findings demonstrate that N88S seipin triggers a futile cycle in which misrouted cytosolic acetyl-CoA drives lipogenesis, amplifying oxidative damage and ER stress. We conclude that defective peroxisome\u2013mitochondria metabolic coupling and acetyl-CoA misrouting may represent central pathogenic mechanisms driving cellular dysfunction in N88S-linked seipinopathy.<\/jats:p>","DOI":"10.3390\/cells15050395","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T15:05:27Z","timestamp":1771945527000},"page":"395","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Impaired Acetyl-CoA Compartmentalization Drives a Futile Lipogenic\u2013Oxidative Cycle in N88S Seipinopathy"],"prefix":"10.3390","volume":"15","author":[{"given":"V\u00edtor","family":"Moreira","sequence":"first","affiliation":[{"name":"i3S Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal"}]},{"given":"Carlo W. T.","family":"van Roermund","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7868-4663","authenticated-orcid":false,"given":"V\u00edtor","family":"Costa","sequence":"additional","affiliation":[{"name":"i3S Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2179-2946","authenticated-orcid":false,"given":"Vitor","family":"Teixeira","sequence":"additional","affiliation":[{"name":"i3S Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/s41574-023-00845-0","article-title":"Lipid droplet biogenesis and functions in health and disease","volume":"19","author":"Zadoorian","year":"2023","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41580-018-0085-z","article-title":"Dynamics and functions of lipid droplets","volume":"20","author":"Olzmann","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101141","DOI":"10.1016\/j.plipres.2021.101141","article-title":"Hello from the other side: Membrane contact of lipid droplets with other organelles and subsequent functional implications","volume":"85","author":"Costa","year":"2022","journal-title":"Prog. Lipid Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1083\/jcb.200711136","article-title":"Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast","volume":"180","author":"Fei","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1083\/jcb.201502070","article-title":"The seipin complex Fld1\/Ldb16 stabilizes ER-lipid droplet contact sites","volume":"211","author":"Grippa","year":"2015","journal-title":"J. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.15252\/embj.201695170","article-title":"Seipin regulates ER-lipid droplet contacts and cargo delivery","volume":"35","author":"Salo","year":"2016","journal-title":"EMBO J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"158820","DOI":"10.1016\/j.bbalip.2020.158820","article-title":"Leading the way in the nervous system: Lipid Droplets as new players in health and disease","volume":"1866","author":"Teixeira","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.5692\/clinicalneurol.51.1186","article-title":"BSCL2-related neurologic disorders\/seipinopathy: Endoplasmic reticulum stress in neurodegeneration","volume":"51","author":"Ito","year":"2011","journal-title":"Rinsho Shinkeigaku"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/ng1313","article-title":"Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome","volume":"36","author":"Windpassinger","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1002\/ana.21070","article-title":"Molecular pathogenesis of seipin\/BSCL2-related motor neuron diseases","volume":"61","author":"Ito","year":"2007","journal-title":"Ann. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.nbd.2008.05.004","article-title":"Characterization of seipin\/BSCL2, a protein associated with spastic paraplegia 17","volume":"31","author":"Ito","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.1093\/hmg\/ddr304","article-title":"N88S seipin mutant transgenic mice develop features of seipinopathy\/BSCL2-related motor neuron disease via endoplasmic reticulum stress","volume":"20","author":"Yagi","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1093\/hmg\/ddr497","article-title":"Characterization of inclusion bodies with cytoprotective properties formed by seipinopathy-linked mutant seipin","volume":"21","author":"Ito","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e535","DOI":"10.1038\/cddis.2013.64","article-title":"Motor neuron degeneration in a mouse model of seipinopathy","volume":"4","author":"Guo","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12964-024-02007-9","article-title":"N88S seipin-related seipinopathy is a lipidopathy associated with loss of iron homeostasis","volume":"23","author":"Ribeiro","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.freeradbiomed.2022.09.009","article-title":"Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathy","volume":"192","author":"Nogueira","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","first-page":"1719","article-title":"Oxidative stress in N88S seipinopathy: Novel insights into the mechanisms of neurodegeneration and therapeutic avenues","volume":"18","author":"Costa","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13195-020-00680-9","article-title":"Association of lysophosphatidic acids with cerebrospinal fluid biomarkers and progression to Alzheimer\u2019s disease","volume":"12","author":"Ahmad","year":"2020","journal-title":"Alzheimers Res. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dedoni, S., Avdoshina, V., Olianas, M.C., and Onali, P. (2025). Role of Lysophosphatidic Acid in Neurological Diseases: From Pathophysiology to Therapeutic Implications. Front. Biosci., 30.","DOI":"10.31083\/FBL28245"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/acschemneuro.7b00314","article-title":"Novel Trimodal MALDI Imaging Mass Spectrometry (IMS3) at 10 mum Reveals Spatial Lipid and Peptide Correlates Implicated in Abeta Plaque Pathology in Alzheimer\u2019s Disease","volume":"8","author":"Kaya","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s00418-023-02259-5","article-title":"The peroxisome: An update on mysteries 3.0","volume":"161","author":"Kumar","year":"2024","journal-title":"Histochem. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/1873-3468.13340","article-title":"The peroxisome biogenesis factors Pex3 and Pex19: Multitasking proteins with disputed functions","volume":"593","author":"Jansen","year":"2019","journal-title":"FEBS Lett."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Wang, Z., Su, C., Zhang, Y., Shangguan, S., Wang, R., and Su, J. (2023). Key enzymes involved in the utilization of fatty acids by Saccharomyces cerevisiae: A review. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1294182"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ceb.2015.02.003","article-title":"Acetyl-CoA and the regulation of metabolism: Mechanisms and consequences","volume":"33","author":"Shi","year":"2015","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1432-1033.1969.tb00658.x","article-title":"Studies on the regulation and localization of the glyoxylate cycle enzymes in Saccharomyces cerevisiae","volume":"10","author":"Duntze","year":"1969","journal-title":"Eur. J. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1128\/jb.106.3.908-914.1971","article-title":"Activities of tricarboxylic acid cycle enzymes, glyoxylate cycle enzymes, and fructose diphosphatase in bakers\u2019 yeast during adaptation to acetate oxidation","volume":"106","author":"Gosling","year":"1971","journal-title":"J. Bacteriol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/978-1-0716-1266-8_6","article-title":"Analysis of Mitochondrial Retrograde Signaling in Yeast Model Systems","volume":"2276","author":"Guaragnella","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.molcel.2015.04.013","article-title":"The Ubiquitin Ligase SCF(Ucc1) Acts as a Metabolic Switch for the Glyoxylate Cycle","volume":"59","author":"Nakatsukasa","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s44324-024-00045-y","article-title":"Pulling back the mitochondria\u2019s iron curtain","volume":"3","author":"Shkuri","year":"2025","journal-title":"npj Metab. Health Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/s41392-024-02095-6","article-title":"Redox regulation: Mechanisms, biology and therapeutic targets in diseases","volume":"10","author":"Li","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1515\/hsz-2022-0223","article-title":"Comparison of human PEX knockout cell lines suggests a dual role of PEX1 in peroxisome biogenesis","volume":"404","author":"Ott","year":"2023","journal-title":"Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1111\/acel.12113","article-title":"The significance of peroxisome function in chronological aging of Saccharomyces cerevisiae","volume":"12","author":"Lefevre","year":"2013","journal-title":"Aging Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"102917","DOI":"10.1016\/j.redox.2023.102917","article-title":"Glutathione and peroxisome redox homeostasis","volume":"67","author":"Ferreira","year":"2023","journal-title":"Redox Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1007\/s11745-004-1278-3","article-title":"Beta-oxidation, esterification, and secretion of radiolabeled fatty acids in cultivated Atlantic salmon skeletal muscle cells","volume":"39","author":"Vegusdal","year":"2004","journal-title":"Lipids"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/0092-8674(93)90050-Z","article-title":"RTG1 and RTG2: Two yeast genes required for a novel path of communication from mitochondria to the nucleus","volume":"72","author":"Liao","year":"1993","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/yea.1828","article-title":"TCA cycle-independent acetate metabolism via the glyoxylate cycle in Saccharomyces cerevisiae","volume":"28","author":"Lee","year":"2011","journal-title":"Yeast"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1126\/science.1218099","article-title":"A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans","volume":"337","author":"Bricker","year":"2012","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.ymben.2014.11.009","article-title":"Microbial acetyl-CoA metabolism and metabolic engineering","volume":"28","author":"Krivoruchko","year":"2015","journal-title":"Metab. Eng."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5843","DOI":"10.1093\/emboj\/18.21.5843","article-title":"Molecular characterization of carnitine-dependent transport of acetyl-CoA from peroxisomes to mitochondria in Saccharomyces cerevisiae and identification of a plasma membrane carnitine transporter, Agp2p","volume":"18","author":"Hettema","year":"1999","journal-title":"EMBO J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/j.1574-6968.2006.00548.x","article-title":"Modulating aroma compounds during wine fermentation by manipulating carnitine acetyltransferases in Saccharomyces cerevisiae","volume":"267","author":"Cordente","year":"2007","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"16348","DOI":"10.1016\/S0021-9258(17)34014-0","article-title":"Biochemical studies of three Saccharomyces cerevisiae acyl-CoA synthetases, Faa1p, Faa2p, and Faa3p","volume":"269","author":"Knoll","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"18037","DOI":"10.1016\/S0021-9258(17)32414-6","article-title":"Genetic analysis of the role of Saccharomyces cerevisiae acyl-CoA synthetase genes in regulating protein N-myristoylation","volume":"269","author":"Johnson","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1038\/s12276-020-00539-x","article-title":"Histone acylation marks respond to metabolic perturbations and enable cellular adaptation","volume":"52","author":"Jo","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_44","first-page":"1214","article-title":"Control of lipid droplet size in budding yeast requires the collaboration between Fld1 and Ldb16","volume":"127","author":"Wang","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/aps.2014.164","article-title":"Seipin mutation at glycosylation sites activates autophagy in transfected cells via abnormal large lipid droplets generation","volume":"36","author":"Fan","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1002\/(SICI)1097-0061(199807)14:10<953::AID-YEA293>3.0.CO;2-U","article-title":"Additional modules for versatile and economical PCR-based gene deletion and modification in Saccharomyces cerevisiae","volume":"14","author":"Longtine","year":"1998","journal-title":"Yeast"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1002\/yea.1142","article-title":"A versatile toolbox for PCR-based tagging of yeast genes: New fluorescent proteins, more markers and promoter substitution cassettes","volume":"21","author":"Janke","year":"2004","journal-title":"Yeast"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/yea.2998","article-title":"Primers-4-Yeast: A comprehensive web tool for planning primers for Saccharomyces cerevisiae","volume":"31","author":"Yofe","year":"2014","journal-title":"Yeast"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Li, D., Yang, S.G., He, C.W., Zhang, Z.T., Liang, Y., Li, H., Zhu, J., Su, X., Gong, Q., and Xie, Z. (2020). Excess diacylglycerol at the endoplasmic reticulum disrupts endomembrane homeostasis and autophagy. BMC Biol., 18.","DOI":"10.1186\/s12915-020-00837-w"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nprot.2007.13","article-title":"High-efficiency yeast transformation using the LiAc\/SS carrier DNA\/PEG method","volume":"2","author":"Gietz","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Teixeira, V., Martins, T.S., Prinz, W.A., and Costa, V. (2021). Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22169017"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Turkolmez, S., Chornyi, S., Alhajouj, S., IJlst, L., Waterham, H.R., Mitchell, P.J., Hettema, E.H., and van Roermund, C.W.T. (2023). Peroxisomal NAD(H) Homeostasis in the Yeast Debaryomyces hansenii Depends on Two Redox Shuttles and the NAD+ Carrier, Pmp47. Biomolecules, 13.","DOI":"10.3390\/biom13091294"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.biochi.2003.10.019","article-title":"Inhibition of Krebs cycle and activation of glyoxylate cycle in the course of chronological aging of Saccharomyces cerevisiae. Compensatory role of succinate oxidation","volume":"86","author":"Samokhvalov","year":"2004","journal-title":"Biochimie"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"fnu042","DOI":"10.1093\/femsle\/fnu042","article-title":"Overexpression of acetyl-CoA synthetase in Saccharomyces cerevisiae increases acetic acid tolerance","volume":"362","author":"Ding","year":"2015","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1099\/00221287-140-3-569","article-title":"Stress tolerance and membrane lipid unsaturation in Saccharomyces cerevisiae grown aerobically or anaerobically","volume":"140","author":"Steels","year":"1994","journal-title":"Microbiology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6175","DOI":"10.1038\/s41598-018-24466-0","article-title":"Visualizing multiple inter-organelle contact sites using the organelle-targeted split-GFP system","volume":"8","author":"Kakimoto","year":"2018","journal-title":"Sci. Rep."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/5\/395\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T10:22:12Z","timestamp":1772533332000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/5\/395"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,24]]},"references-count":56,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["cells15050395"],"URL":"https:\/\/doi.org\/10.3390\/cells15050395","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,24]]}}}