{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:27:11Z","timestamp":1787128031372,"version":"build-2736575974"},"reference-count":65,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangzhou postdoctoral funds"},{"name":"Guangzhou Huangpu District postdoctoral funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Apoptosis is traditionally considered a definitive barrier against oncogenesis, as caspase activation typically eliminates damaged and genetically unstable cells. Here, we report that caspase-8, an initiator of extrinsic apoptosis, paradoxically promotes genetic instability and carcinogenesis following exposure to radiation. We observed that a substantial fraction of mammalian cells exposed to ionizing radiation can survive despite caspase-8 activation. This sublethal activation of caspase-8 facilitated persistent DNA damage, which was attenuated by the expression of a dominant-negative caspase-8 (C360A, Casp8DN) or short hairpin RNA (shRNA)-mediated knockdown of caspase-8 in mammalian cells. The facilitative role of caspase-8 in radiation-induced genomic instability was further validated in caspase-8 heterozygous mice. Moreover, inhibition of caspase-8 abolished iron-ion radiation-induced oncogenic transformation in both soft agar and nude mice. Mechanistically, sublethal caspase-8 activation promoted the nuclear translocation of mitochondrial endonuclease G and persistent DNA damage, accompanied by activation of non-canonical nuclear factor \u03baB (NF-\u03baB) signaling. Collectively, our findings demonstrate that caspase-8 can act as a causative driver of radiation-induced malignancy, challenging the dogma of caspases as universal anticancer barriers and providing important insights into the long-term health risks associated with space radiation and radiotherapy.<\/jats:p>","DOI":"10.3390\/ijms27167398","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T07:58:23Z","timestamp":1787126303000},"page":"7398","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sublethal Caspase-8 Activation Drives Radiation-Induced Genetic Instability and Oncogenic Transformation Through Endonuclease G and Non-Canonical NF-\u03baB Signaling"],"prefix":"10.3390","volume":"27","author":[{"given":"Chenchen","family":"Zhu","sequence":"first","affiliation":[{"name":"College of Life Science and Technology, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan-Yuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renwei","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9918-2865","authenticated-orcid":false,"given":"Yifei","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/imr.12541","article-title":"Caspase-8: Regulating life and death","volume":"277","author":"Tummers","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5805","DOI":"10.1007\/s12035-023-03433-5","article-title":"A review on caspases: Key regulators of biological activities and apoptosis","volume":"60","author":"Sahoo","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.molcel.2012.05.004","article-title":"A death effector domain chain DISC model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death","volume":"47","author":"Dickens","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_5","first-page":"954","article-title":"Structural and functional roles of caspase-8 in extrinsic apoptosis","volume":"31","author":"Ha","year":"2021","journal-title":"J. Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"110110","DOI":"10.1016\/j.fsi.2024.110110","article-title":"FADD cooperates with Caspase-8 to positively regulate the innate immune response and promote apoptosis following bacterial infection in Japanese eel","volume":"157","author":"Wang","year":"2025","journal-title":"Fish. Shellfish Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"32608","DOI":"10.1074\/jbc.273.49.32608","article-title":"Inhibition of human caspases by peptide-based and macromolecular inhibitors","volume":"273","author":"Peterson","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/376037a0","article-title":"Identification and inhibition of the ICE\/CED-3 protease necessary for mammalian apoptosis","volume":"376","author":"Nicholson","year":"1995","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2976","DOI":"10.4049\/jimmunol.173.5.2976","article-title":"Caspase-8 serves both apoptotic and nonapoptotic roles","volume":"173","author":"Kang","year":"2004","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1126\/science.1104765","article-title":"Requirement for caspase-8 in NF-\u03baB activation by antigen receptor","volume":"307","author":"Su","year":"2005","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"22249","DOI":"10.1073\/pnas.1009751108","article-title":"Development of atopic dermatitis-like skin disease from the chronic loss of epidermal caspase-8","volume":"107","author":"Li","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1038\/sj.cdd.4401090","article-title":"Ex vivo whole-embryo culture of caspase-8-deficient embryos normalize their aberrant phenotypes in the developing neural tube and heart","volume":"9","author":"Sakamaki","year":"2002","journal-title":"Cell Death Differ."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.celrep.2012.03.010","article-title":"Survival function of the FADD-CASPASE-8-cFLIPL complex","volume":"1","author":"Dillon","year":"2012","journal-title":"Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/nature09857","article-title":"RIP3 mediates the embryonic lethality of caspase-8-deficient mice","volume":"471","author":"Kaiser","year":"2011","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/nature09852","article-title":"Catalytic activity of the caspase-8\u2013FLIPL complex inhibits RIPK3-dependent necrosis","volume":"471","author":"Oberst","year":"2011","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/s41586-019-1770-6","article-title":"Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis","volume":"575","author":"Fritsch","year":"2019","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41586-019-1752-8","article-title":"Activity of caspase-8 determines plasticity between cell death pathways","volume":"575","author":"Newton","year":"2019","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/s41586-019-1548-x","article-title":"Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis","volume":"574","author":"Newton","year":"2019","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11926","DOI":"10.1073\/pnas.1820529116","article-title":"Caspase-8 promotes c-Rel\u2013dependent inflammatory cytokine expression and resistance against Toxoplasma gondii","volume":"116","author":"DeLaney","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11280","DOI":"10.1038\/s41467-025-67142-4","article-title":"Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression","volume":"16","author":"Androulidaki","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_21","first-page":"1562","article-title":"Histone deacetylase inhibitors overcome TRAIL resistance in cancers with epigenetic silencing of caspase-8 by restoring caspase-8 expression","volume":"68","author":"Haecker","year":"2008","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ccr.2008.02.003","article-title":"Yes and PI3K bind CD95 to signal invasion of glioblastoma","volume":"13","author":"Kleber","year":"2008","journal-title":"Cancer Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"20664","DOI":"10.1074\/jbc.M111.326058","article-title":"Fas ligand enhances malignant behavior of tumor cells through interaction with Met, hepatocyte growth factor receptor, in lipid rafts","volume":"287","author":"Lin","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"ra13","DOI":"10.1126\/scisignal.2000634","article-title":"Apoptotic cells activate the \u201cphoenix rising\u201d pathway to promote wound healing and tissue regeneration","volume":"3","author":"Li","year":"2010","journal-title":"Sci. Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1038\/cr.2017.41","article-title":"Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells","volume":"27","author":"Liu","year":"2017","journal-title":"Cell Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nm.2385","article-title":"Caspase 3\u2013mediated stimulation of tumor cell repopulation during cancer radiotherapy","volume":"17","author":"Huang","year":"2011","journal-title":"Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.molcel.2015.01.018","article-title":"Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death","volume":"57","author":"Ichim","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.molcel.2015.03.003","article-title":"Caspase-3 promotes genetic instability and carcinogenesis","volume":"58","author":"Liu","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nrc2391","article-title":"Heavy ion carcinogenesis and human space exploration","volume":"8","author":"Durante","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1667\/RR1673.1","article-title":"Threshold-type dose response for induction of neoplastic transformation by 1 GeV\/nucleon iron ions","volume":"171","author":"Elmore","year":"2009","journal-title":"Radiat. Res."},{"key":"ref_31","first-page":"103","article-title":"Synthesis, enzymatic evaluation, and docking studies of fluorogenic caspase 8 tetrapeptide substrates","volume":"5","author":"Reszka","year":"2010","journal-title":"ChemMedChem Chem. Enabling Drug Discov."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1007\/s10967-025-09980-6","article-title":"Differential cell death pathways in normal and cancerous breast cells response to direct X-ray irradiation and bystander effects","volume":"334","author":"Alton","year":"2025","journal-title":"J. Radioanal. Nucl. Chem."},{"key":"ref_33","first-page":"3223","article-title":"Gene expression profiling of MCF10A breast epithelial cells exposed to IOERT","volume":"35","author":"Minafra","year":"2015","journal-title":"Anticancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"25719","DOI":"10.1074\/jbc.272.41.25719","article-title":"Biochemical characteristics of caspases-3,-6,-7, and-8","volume":"272","author":"Stennicke","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S1074-7613(00)80609-3","article-title":"Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas\/Apo1, and DR3 and is lethal prenatally","volume":"9","author":"Varfolomeev","year":"1998","journal-title":"Immunity"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41419-024-06884-3","article-title":"Caspase-3 promotes oncogene-induced malignant transformation via EndoG-dependent Src-STAT3 phosphorylation","volume":"15","author":"Zhu","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.bbamcr.2011.01.026","article-title":"Caspase-8 and bid: Caught in the act between death receptors and mitochondria","volume":"1813","author":"Kantari","year":"2011","journal-title":"Biochim. Biophys. Acta BBA-Mol. Cell Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"15053","DOI":"10.1038\/cddiscovery.2015.53","article-title":"A dual role for Caspase8 and NF-\u03baB interactions in regulating apoptosis and necroptosis of ovarian cancer, with correlation to patient survival","volume":"1","author":"Hernandez","year":"2015","journal-title":"Cell Death Discov."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e22593","DOI":"10.7554\/eLife.22593","article-title":"Caspase-8 contributes to angiogenesis and chemotherapy resistance in glioblastoma","volume":"6","author":"Fianco","year":"2017","journal-title":"eLife"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1158\/0008-5472.815.65.3","article-title":"CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas","volume":"65","author":"Soung","year":"2005","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1111\/cas.12191","article-title":"Cancer-associated missense mutations of caspase-8 activate nuclear factor-\u03baB signaling","volume":"104","author":"Ando","year":"2013","journal-title":"Cancer Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1016\/j.cellsig.2007.05.016","article-title":"Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain","volume":"19","author":"Feng","year":"2007","journal-title":"Cell. Signal."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Vesela, B., Killinger, M., Rihova, K., Benes, P., Svandov\u00e1, E., Kratochvilov\u00e1, A., Trcka, F., Kleparnik, K., and Matalova, E. (2022). Caspase-8 deficient osteoblastic cells display alterations in non-apoptotic pathways. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.794407"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.diff.2009.05.002","article-title":"Non-canonical role for the TRAIL receptor DR5\/FADD\/caspase pathway in the regulation of MyoD expression and skeletal myoblast differentiation","volume":"78","author":"Ross","year":"2009","journal-title":"Differentiation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1053\/j.gastro.2005.08.007","article-title":"Silencing of caspase-8 in murine hepatocellular carcinomas is mediated via methylation of an essential promoter element","volume":"129","author":"Liedtke","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/s41418-022-01093-x","article-title":"Caspase-8 as a novel mediator linking Src kinase signaling to enhanced glioblastoma malignancy","volume":"30","author":"Contadini","year":"2023","journal-title":"Cell Death Differ."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.canlet.2010.07.022","article-title":"Caspase-8 as a therapeutic target in cancer","volume":"332","author":"Stupack","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3755","DOI":"10.1158\/0008-5472.CAN-08-3937","article-title":"Caspase-8 association with the focal adhesion complex promotes tumor cell migration and metastasis","volume":"69","author":"Barbero","year":"2009","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1126\/science.abi6378","article-title":"Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress","volume":"376","author":"Larsen","year":"2022","journal-title":"Science"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S0092-8674(00)81590-1","article-title":"Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis","volume":"94","author":"Li","year":"1998","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1083\/jcb.200803129","article-title":"Cardiolipin provides an essential activating platform for caspase-8 on mitochondria","volume":"183","author":"Gonzalvez","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/cdd.2010.135","article-title":"BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane","volume":"18","author":"Schug","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s44466-025-00014-0","article-title":"NF-\u03baB: Master regulator of cellular responses in health and disease","volume":"1","author":"Hoffmann","year":"2025","journal-title":"Immun. Inflamm."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Campbell, K.J., O\u2019Shea, J.M., and Perkins, N.D. (2006). Differential regulation of NF-\u03baB activation and function by topoisomerase II inhibitors. BMC Cancer, 6.","DOI":"10.1186\/1471-2407-6-101"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/S1097-2765(04)00131-5","article-title":"Active repression of antiapoptotic gene expression by RelA (p65) NF-\u03baB","volume":"13","author":"Campbell","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2700","DOI":"10.1093\/nar\/gkac104","article-title":"Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction","volume":"50","author":"Bourseguin","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1080\/095530099139593","article-title":"Induction and persistence of chromosomal exchanges in mouse bone marrow cells following whole-body exposure to X-rays","volume":"75","author":"Xiao","year":"1999","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1667\/RR0967.1","article-title":"Relative biological effectiveness of high-energy iron ions for micronucleus formation at low doses","volume":"168","author":"Groesser","year":"2007","journal-title":"Radiat. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1667\/RR1982.1","article-title":"Amifostine metabolite WR-1065 disrupts homologous recombination in mammalian cells","volume":"173","author":"Dziegielewski","year":"2010","journal-title":"Radiat. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"17773","DOI":"10.1073\/pnas.1110969108","article-title":"Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells","volume":"108","author":"Konishi","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/emmm.201000068","article-title":"Aurora-A expressing tumour cells are deficient for homology-directed DNA double strand-break repair and sensitive to PARP inhibition","volume":"2","author":"Sourisseau","year":"2010","journal-title":"EMBO Mol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5858","DOI":"10.1074\/jbc.273.10.5858","article-title":"DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139","volume":"273","author":"Rogakou","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/0006-291X(84)90411-X","article-title":"Microelectrophoretic study of radiation-induced DNA damages in individual mammalian cells","volume":"123","author":"Ostling","year":"1984","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/0014-4827(88)90265-0","article-title":"A simple technique for quantitation of low levels of DNA damage in individual cells","volume":"175","author":"Singh","year":"1988","journal-title":"Exp. Cell Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"86","DOI":"10.2307\/3577587","article-title":"Heterogeneity in radiation-induced DNA damage and repair in tumor and normal cells measured using the \u201ccomet\u201d assay","volume":"122","author":"Olive","year":"1990","journal-title":"Radiat. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7398\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:00:58Z","timestamp":1787126458000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7398"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":65,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167398"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167398","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]}}}