{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:53:14Z","timestamp":1785433994858,"version":"3.56.0"},"reference-count":59,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006827","name":"FLDOH","doi-asserted-by":"publisher","award":["268"],"award-info":[{"award-number":["268"]}],"id":[{"id":"10.13039\/100006827","id-type":"DOI","asserted-by":"publisher"}]},{"award":["268"],"award-info":[{"award-number":["268"]}],"id":[{"id":"https:\/\/ror.org\/03e1xkn26","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["2R01AI132711-06"],"award-info":[{"award-number":["2R01AI132711-06"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2R01AI132711-06"],"award-info":[{"award-number":["2R01AI132711-06"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"USF Provost\u2019s CREATE Award","award":["FY24\u201327"],"award-info":[{"award-number":["FY24\u201327"]}]},{"name":"COPH Research Award"},{"name":"WLP","award":["FY2023"],"award-info":[{"award-number":["FY2023"]}]},{"name":"USF Microbiome Institute Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Heme metabolism is central to the biology of malaria parasites and to the mechanism of action of artemisinin-based therapies. Within malaria-infected red blood cells (RBCs), heme-related chemistry arises from multiple nested metabolic sources that function as \u201cRussian dolls\u201d: the truncated heme biosynthetic capacity of the host erythrocyte, the parasite\u2019s own heme synthesis pathway, and host heme released through hemoglobin digestion in the parasite food vacuole. These overlapping metabolic layers create distinct pools of heme that can influence redox balance and drug activation. Recent studies highlight that exogenous 5-aminolevulinic acid (5-ALA) can perturb host heme biosynthesis in infected erythrocytes, potentially increasing intracellular levels of the heme intermediate protoporphyrin IX and sensitizing parasites to oxidative stress. However, the extent to which such metabolic perturbations affect artemisinin susceptibility depends strongly on parasite stage and exposure duration. Here we review the compartmentalized architecture of heme metabolism in malaria-infected RBCs and discuss how these nested vulnerabilities may be exploited for therapeutic intervention.<\/jats:p>","DOI":"10.3390\/pathogens15050477","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:43:51Z","timestamp":1777448631000},"page":"477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Russian Dolls of Heme Metabolism in Malaria-Infected Red Blood Cells: Nested Vulnerabilities and Therapeutic Opportunities"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3313-2782","authenticated-orcid":false,"given":"Swamy R.","family":"Adapa","sequence":"first","affiliation":[{"name":"Department of Global, Environmental, and Genomic Health Sciences, College of Public Health, University of South Florida, Tampa, FL 33612, USA"},{"name":"USF Genomics Program, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faiza A.","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8982-4169","authenticated-orcid":false,"given":"Rays H. Y.","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Global, Environmental, and Genomic Health Sciences, College of Public Health, University of South Florida, Tampa, FL 33612, USA"},{"name":"USF Genomics Program, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1126\/science.aap7847","article-title":"Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis","volume":"360","author":"Zhang","year":"2018","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s00430-012-0272-z","article-title":"Malaria and human red blood cells","volume":"201","author":"Mohandas","year":"2012","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1021\/acsomega.2c06768","article-title":"Oxidants and Antioxidants in the Redox Biochemistry of Human Red Blood Cells","volume":"8","author":"Orrico","year":"2023","journal-title":"ACS Omega"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"111103","DOI":"10.1016\/j.celrep.2022.111103","article-title":"The protein organization of a red blood cell","volume":"40","author":"McCafferty","year":"2022","journal-title":"Cell Rep."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Fratz, E.J., Hunter, G.A., and Ferreira, G.C. (2014). Expression of Murine 5-Aminolevulinate Synthase Variants Causes Protoporphyrin IX Accumulation and Light-Induced Mammalian Cell Death. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093078"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/S0003-2697(03)00175-1","article-title":"A continuous anaerobic fluorimetric assay for ferrochelatase by monitoring porphyrin disappearance","volume":"318","author":"Shi","year":"2003","journal-title":"Anal. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"44660","DOI":"10.1074\/jbc.M203584200","article-title":"Transient State Kinetic Investigation of 5-Aminolevulinate Synthase Reaction Mechanism","volume":"277","author":"Zhang","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Pignatelli, P., Umme, S., D\u2019Antonio, D.L., Piattelli, A., and Curia, M.C. (2023). Reactive Oxygen Species Produced by 5-Aminolevulinic Acid Photodynamic Therapy in the Treatment of Cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108964"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e16959","DOI":"10.15252\/emmm.202216959","article-title":"A whole-genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors","volume":"15","author":"Orthofer","year":"2023","journal-title":"EMBO Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4899","DOI":"10.1021\/cr078274t","article-title":"Interplay between malaria; crystalline hemozoin formation, and antimalarial drug action and design","volume":"108","author":"Weissbuch","year":"2008","journal-title":"Chem. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0162-0134(02)00372-0","article-title":"Physico-chemical aspects of hemozoin (malaria pigment) structure and formation","volume":"91","author":"Egan","year":"2002","journal-title":"J. Inorg. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10111","DOI":"10.1038\/ncomms10111","article-title":"Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum","volume":"6","author":"Wang","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-308X(01)50029-9","article-title":"The malaria-infected red blood cell: Structural and functional changes","volume":"50","author":"Cooke","year":"2001","journal-title":"Adv. Parasitol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Siddiqui, F.A., Adapa, S.R., Li, X., Miao, J., Cui, L., and Jiang, R.H.Y. (2026). Targeting Infected Host Cell Heme Metabolism to Kill Malaria Parasites. Pharmaceuticals, 19.","DOI":"10.3390\/ph19010167"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e09143","DOI":"10.7554\/eLife.09143","article-title":"Deconvoluting heme biosynthesis to target blood-stage malaria parasites","volume":"4","author":"Sigala","year":"2015","journal-title":"eLife"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nagaraj, V.A., Sundaram, B., Varadarajan, N.M., Subramani, P.A., Kalappa, D.M., Ghosh, S.K., and Padmanaban, G. (2013). Malaria parasite-synthesized heme is essential in the mosquito and liver stages and complements host heme in the blood stages of infection. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003522"},{"key":"ref_17","unstructured":"Banerjee, R., and Goldberg, D.E. (2001). Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery, Springer."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.abb.2018.02.015","article-title":"Ferrochelatase \u03c0-helix: Implications from examining the role of the conserved \u03c0-helix glutamates in porphyrin metalation and product release","volume":"644","author":"Gillam","year":"2018","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1142\/S1088424616500395","article-title":"The conserved active site histidine-glutamate pair of ferrochelatase coordinately catalyzes porphyrin metalation","volume":"20","author":"Hunter","year":"2016","journal-title":"J. Porphyr. Phthalocyanines"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1021\/acs.jproteome.7b00025","article-title":"Quantitative Analysis of Human Red Blood Cell Proteome","volume":"16","author":"Bryk","year":"2017","journal-title":"J. Proteome Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/BF02110029","article-title":"Heme biosynthesis: Biochemistry; molecular biology, and relationship to disease","volume":"27","author":"Ferreira","year":"1995","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/s42003-023-05024-5","article-title":"A PPIX-binding probe facilitates discovery of PPIX-induced cell death modulation by peroxiredoxin","volume":"6","author":"Lynch","year":"2023","journal-title":"Commun. Biol."},{"key":"ref_23","unstructured":"St\u00f6lzel, U., Kubisch, I., Stauch, T., and Schuppan, D. (2022). Physician\u2019s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, Springer."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.jinorgbio.2007.12.004","article-title":"Recent advances in understanding the mechanism of hemozoin (malaria pigment) formation","volume":"102","author":"Egan","year":"2008","journal-title":"J. Inorg. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Adapa, S.R., Sami, A., Meshram, P., Ferreira, G.C., and Jiang, R.H. (2024). Uncovering Porphyrin Accumulation in the Tumor Microenvironment. Genes, 15.","DOI":"10.1101\/2024.04.11.589133"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Adapa, S.R., Porshe, S., Talada, D.P., Nywening, T.M., Anderson, M.L., Shaw, T.I., and Jiang, R.H.Y. (2025). Spatial Transcriptomics Reveals Distinct Architectures but Shared Vulnerabilities in Primary and Metastatic Liver Tumors. Cancers, 17.","DOI":"10.3390\/cancers17193210"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Adapa, S.R., Meshram, P., Sami, A., and Jiang, R.H. (2024). Harnessing Porphyrin Accumulation in Liver Cancer: Combining Genomic Data and Drug Targeting. Biomolecules, 14.","DOI":"10.3390\/biom14080959"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e202302547","DOI":"10.26508\/lsa.202302547","article-title":"Porphyrin overdrive rewires cancer cell metabolism","volume":"7","author":"Adapa","year":"2024","journal-title":"Life Sci. Alliance"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1007\/s00277-021-04575-z","article-title":"Concise review: How do red blood cells born, live, and die?","volume":"100","author":"Corrons","year":"2021","journal-title":"Ann. Hematol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.ymgme.2019.06.003","article-title":"5-Aminolevulinate synthase catalysis: The catcher in heme biosynthesis","volume":"128","author":"Stojanovski","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1159\/000366383","article-title":"Protoporphyrin IX induces a necrotic cell death in human THP-1 macrophages through activation of reactive oxygen species\/c-Jun N-terminal protein kinase pathway and opening of mitochondrial permeability transition pore","volume":"34","author":"Xu","year":"2014","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"D\u2019alessandro, A., Anastasiadi, A.T., Tzounakas, V.L., Nemkov, T., Reisz, J.A., Kriebardis, A.G., Zimring, J.C., Spitalnik, S.L., and Busch, M.P. (2023). Red Blood Cell Metabolism In Vivo and In Vitro. Metabolites, 13.","DOI":"10.3390\/metabo13070793"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3278","DOI":"10.1111\/febs.14192","article-title":"Characterization of plasma labile heme in hemolytic conditions","volume":"284","author":"Gouveia","year":"2017","journal-title":"FEBS J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.coi.2015.11.006","article-title":"Red alert: Labile heme is an alarmin","volume":"38","author":"Soares","year":"2016","journal-title":"Curr. Opin. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5624","DOI":"10.1039\/C9CS00268E","article-title":"Heme: Emergent roles of heme in signal transduction, functional regulation and as catalytic centres","volume":"48","author":"Shimizu","year":"2019","journal-title":"Chem. Soc. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Comer, J.M., and Zhang, L. (2018). Experimental methods for studying cellular heme signaling. Cells, 7.","DOI":"10.3390\/cells7060047"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1021\/acs.biochem.7b00007","article-title":"Heme gazing: Illuminating eukaryotic heme trafficking, dynamics, and signaling with fluorescent heme sensors","volume":"56","author":"Hanna","year":"2017","journal-title":"Biochemistry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1126\/science.aax4735","article-title":"A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites","volume":"367","author":"Birnbaum","year":"2020","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Gibbons, J., Button-Simons, K.A., Adapa, S.R., Li, S., Pietsch, M., Zhang, M., Liao, X., Adams, J.H., Ferdig, M.T., and Jiang, R.H.Y. (2018). Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum. BMC Genom., 19.","DOI":"10.1186\/s12864-018-5207-7"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/j.1365-2958.2007.05753.x","article-title":"Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites","volume":"65","author":"Hunt","year":"2007","journal-title":"Mol. Microbiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1056\/NEJMoa1513137","article-title":"A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms","volume":"374","author":"Khim","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.ijpddr.2021.05.007","article-title":"Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook","volume":"16","author":"Siddiqui","year":"2021","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/s41598-023-27417-6","article-title":"Protein KIC5 is a novel regulator of artemisinin stress response in the malaria parasite Plasmodium falciparum","volume":"13","author":"Simmons","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Zhu, P., and Zhou, B. (2022). The Antagonizing Role of Heme in the Antimalarial Function of Artemisinin: Elevating Intracellular Free Heme Negatively Impacts Artemisinin Activity in Plasmodium falciparum. Molecules, 27.","DOI":"10.3390\/molecules27061755"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.radphyschem.2009.06.036","article-title":"Characterization of reactive oxygen species generated by protoporphyrin IX under X-ray irradiation","volume":"78","author":"Takahashi","year":"2009","journal-title":"Radiat. Phys. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1124\/jpet.115.228130","article-title":"Protoporphyrin IX: The Good, the Bad, and the Ugly","volume":"356","author":"Sachar","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/bjc.1997.450","article-title":"Factors affecting aminolaevulinic acid-induced generation of protoporphyrin IX","volume":"76","author":"Wyld","year":"1997","journal-title":"Br. J. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1038\/s44321-026-00388-7","article-title":"5-ALA does not potentiate dihydroartemisinin against Plasmodium falciparum malaria parasites","volume":"18","author":"Behrens","year":"2026","journal-title":"EMBO Mol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2564","DOI":"10.1128\/AAC.01466-08","article-title":"Colorimetric High-Throughput Screen for Detection of Heme Crystallization Inhibitors","volume":"53","author":"Rush","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"10107","DOI":"10.1021\/bi101397u","article-title":"The neutral lipid composition present in the digestive vacuole of Plasmodium falciparum concentrates heme and mediates \u03b2-hematin formation with an unusually low activation energy","volume":"49","author":"Hoang","year":"2010","journal-title":"Biochemistry"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1016\/j.bbagen.2014.02.009","article-title":"Malarial hemozoin: From target to tool","volume":"1840","author":"Coronado","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1126\/science.1175667","article-title":"Chloroquine Transport via the Malaria Parasite\u2019s Chloroquine Resistance Transporter","volume":"325","author":"Martin","year":"2009","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.pt.2012.08.002","article-title":"PfCRT and its role in antimalarial drug resistance","volume":"28","author":"Ecker","year":"2012","journal-title":"Trends Parasitol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S1097-2765(05)00077-8","article-title":"Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance","volume":"6","author":"Fidock","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e57","DOI":"10.1182\/blood-2010-07-299636","article-title":"Pathophysiology of sickle cell disease is mirrored by the red blood cell metabolome","volume":"117","author":"Darghouth","year":"2011","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.freeradbiomed.2013.08.181","article-title":"Oxidative stress in sickle cell disease: An overview of erythrocyte redox metabolism and current antioxidant therapeutic strategies","volume":"65","author":"Silva","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.redox.2015.07.018","article-title":"Oxidative stress in \u03b2-thalassaemia and sickle cell disease","volume":"6","author":"Voskou","year":"2015","journal-title":"Redox Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"24064","DOI":"10.1038\/s41598-024-72427-7","article-title":"Computational approach for decoding malaria drug targets from single-cell transcriptomics and finding potential drug molecule","volume":"14","author":"Choudhuri","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.pt.2025.04.006","article-title":"Malaria parasite phenotypic heterogeneity and the power of single-cell technologies","volume":"41","author":"Gyamfi","year":"2025","journal-title":"Trends Parasitol."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/5\/477\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T08:29:39Z","timestamp":1777451379000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/5\/477"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":59,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["pathogens15050477"],"URL":"https:\/\/doi.org\/10.3390\/pathogens15050477","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]}}}