{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:55:47Z","timestamp":1790618147436,"version":"4.1.0"},"reference-count":65,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Sepsis-induced disseminated intravascular coagulation (DIC) carries approximately 44% mortality and has no targeted mechanistic therapy. Stable isotope tracer data show whole-blood glutathione (GSH) synthesis falling by approximately 60% in sepsis despite paradoxically elevated cysteine flux, consistent with enzymatic failure at the glutamate-cysteine ligase (GCL) step rather than substrate shortage. We propose that GCL failure may unify endothelial coagulopathy and innate immune dysfunction in DIC, linked to the NLRP3\/GSDMD pyroptotic coagulation pathway through both cytosolic synthesis and mitochondrial import failure. Cross-dataset bioinformatic analysis was conducted across four independent GEO datasets. Three whole-blood cohorts (n = 200; 144 sepsis, 56 controls; two platforms) were selected for this study (two adult cohorts and one pediatric cohort). All cohorts were strictly filtered to day 1 baseline samples to prevent pseudoreplication. Differential expression was evaluated via Mann\u2013Whitney U with Benjamini\u2013Hochberg correction, with xCell deconvolution resolving bulk signals into cell-type-specific components via Spearman\u2019s correlation. Mitochondrial GSH transporter and receptor-mediated mitophagy genes were evaluated using the same pipeline as an independent evidential layer. A fourth dataset of isolated monocytes (GSE46955; n = 14 individuals, 22 samples) was analyzed to assess AFG3L2 and SLC25A39 co-transcription. Across cohorts, NLRP3 transcript abundance positively correlated with monocyte and neutrophil enrichment scores (e.g., rho = +0.633 and +0.537). Conversely, transcripts for GCLC (rho = \u22120.530) and SLC25A39 (rho = \u22120.400), the principal mitochondrial GSH importer, inversely correlated with these same myeloid population scores. Furthermore, the receptor-mediated mitophagy transcripts FUNDC1 and BNIP3L were significantly downregulated and inversely correlated with expanding myeloid fractions. These bulk transcriptomic patterns reveal a strong inverse relationship between the expression of inflammasome components and GSH synthesis, import, and clearance machinery, though further studies are required to confirm functional protein activation or enzymatic failure. Longitudinal analysis of isolated monocytes, utilizing a linear mixed-effects model to account for repeated within-patient sampling, demonstrated significant aggregate co-transcription between AFG3L2 and SLC25A39 (p = 0.012), indicating tight co-regulation of the importer and its protease. These findings, derived from sepsis-versus-control cohorts without DIC adjudication, suggest that the transcriptional suppression of GSH synthesis and mitochondrial import machinery correlates strongly with NLRP3 and GSDMD transcript upregulation in estimated myeloid populations. Extending this axis to a mechanistic role in DIC is a hypothesis supported by the independent literature, not a direct finding of the present dataset. Because this bottleneck appears enzymatic rather than substrate-dependent, N-acetylcysteine alone may be insufficient to restore homeostasis. We therefore hypothesize that combining intravenous glutathione with an Fe\u2013S cluster-promoting agent, such as hinokitiol, could mechanistically address these findings. However, this remains strictly a preclinical hypothesis that requires extensive investigation to resolve existing safety concerns, particularly the potential for ionophore toxicity in humans.<\/jats:p>","DOI":"10.3390\/ijms27198642","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"8642","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Enzymatic\/Mitochondrial Import Bottleneck in Sepsis with Possible Extensions to DIC: IV Glutathione and Hinokitiol as Potential Therapeutic Candidates"],"prefix":"10.3390","volume":"27","author":[{"given":"Felix","family":"Badiu","sequence":"first","affiliation":[{"name":"Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science and Technology of T\u00e2rgu Mure\u0219, 540139 T\u00e2rgu Mure\u0219, Romania"}],"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"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3767-4861","authenticated-orcid":false,"given":"Mark","family":"Slevin","sequence":"additional","affiliation":[{"name":"Centre for Advanced Medical and Pharmaceutical Research, George Emil Palade University of Medicine, Pharmacy, Science and Technology of T\u00e2rgu Mure\u0219, 540139 T\u00e2rgu Mure\u0219, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.thromres.2016.11.007","article-title":"Coagulation and Sepsis","volume":"149","author":"Levi","year":"2017","journal-title":"Thromb. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2356","DOI":"10.1016\/j.jtha.2025.03.038","article-title":"Updated Definition and Scoring of Disseminated Intravascular Coagulation in 2025: Communication from the ISTH SSC Subcommittee on Disseminated Intravascular Coagulation","volume":"23","author":"Iba","year":"2025","journal-title":"J. Thromb. Haemost."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tsantes, A.G., Parastatidou, S., Tsantes, E.A., Bonova, E., Tsante, K.A., Mantzios, P.G., Vaiopoulos, A.G., Tsalas, S., Konstantinidi, A., and Houhoula, D. (2023). Sepsis-Induced Coagulopathy: An Update on Pathophysiology, Biomarkers, and Current Guidelines. Life, 13.","DOI":"10.3390\/life13020350"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13613-025-01434-2","article-title":"Biomarkers of Sepsis-Induced Coagulopathy: Diagnostic Insights and Potential Therapeutic Implications","volume":"15","author":"Curtiaud","year":"2025","journal-title":"Ann. Intensive Care"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Aquilano, K., Baldelli, S., and Ciriolo, M.R. (2014). Glutathione: New Roles in Redox Signaling for an Old Antioxidant. Front. Pharmacol., 5.","DOI":"10.3389\/fphar.2014.00196"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6508","DOI":"10.1021\/bi200708w","article-title":"Enzymatic Defects Underlying Hereditary Glutamate Cysteine Ligase Deficiency Are Mitigated by Association of the Catalytic and Regulatory Subunits","volume":"50","author":"Willis","year":"2011","journal-title":"Biochemistry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/s41586-021-04025-w","article-title":"SLC25A39 Is Necessary for Mitochondrial Glutathione Import in Mammalian Cells","volume":"599","author":"Wang","year":"2021","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.molcel.2023.12.008","article-title":"Dual Regulation of SLC25A39 by AFG3L2 and Iron Controls Mitochondrial Glutathione Homeostasis","volume":"84","author":"Shi","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kawase, A., Hatanaka, M., Matsuda, N., Shimada, H., and Iwaki, M. (2022). SLC25A39 and SLC25A40 Expression in Mice with Bile Duct Ligation or Lipopolysaccharide Treatment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158573"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"42939","DOI":"10.1038\/s41598-025-30333-6","article-title":"Mitochondrial Glutathione Transporter SLC25A40 Regulates Macrophage Cytokine Production","volume":"15","author":"Yin","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1091\/mbc.8.9.1699","article-title":"Glutathione Synthetase Is Dispensable for Growth under Both Normal and Oxidative Stress Conditions in the Yeast Saccharomyces Cerevisiae Due to an Accumulation of the Dipeptide Gamma-Glutamylcysteine","volume":"8","author":"Grant","year":"1997","journal-title":"Mol. Biol. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1172\/JCI25790","article-title":"Nrf2 Is a Critical Regulator of the Innate Immune Response and Survival during Experimental Sepsis","volume":"116","author":"Thimmulappa","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1164\/rccm.201102-0271OC","article-title":"Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects against Sepsis","volume":"184","author":"Kong","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1101\/gad.13.1.76","article-title":"Keap1 Represses Nuclear Activation of Antioxidant Responsive Elements by Nrf2 through Binding to the Amino-Terminal Neh2 Domain","volume":"13","author":"Itoh","year":"1999","journal-title":"Genes. Dev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1016\/j.bbagen.2012.09.008","article-title":"Glutathione Synthesis","volume":"1830","author":"Lu","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0140-6736(02)09459-X","article-title":"Association between Mitochondrial Dysfunction and Severity and Outcome of Septic Shock","volume":"360","author":"Brealey","year":"2002","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1016\/S0002-9440(10)61135-2","article-title":"Caspase-3-Dependent Cleavage of the Glutamate-L-Cysteine Ligase Catalytic Subunit during Apoptotic Cell Death","volume":"160","author":"Franklin","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1097\/00003246-200104000-00036","article-title":"Cysteine Metabolism and Whole Blood Glutathione Synthesis in Septic Pediatric Patients","volume":"29","author":"Lyons","year":"2001","journal-title":"Crit. Care Med."},{"key":"ref_20","first-page":"G7","article-title":"GSH Transport in Mitochondria: Defense against TNF-Induced Oxidative Stress and Alcohol-Induced Defect","volume":"273","author":"Kaplowitz","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/S0891-5849(99)00059-3","article-title":"Mitochondrial Glutathione Modulates TNF-Alpha-Induced Endothelial Cell Dysfunction","volume":"27","author":"Chen","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1002\/2211-5463.13307","article-title":"A Brief Overview of BNIP3L\/NIX Receptor-Mediated Mitophagy","volume":"11","author":"Novak","year":"2021","journal-title":"FEBS Open Bio"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/s41419-021-04469-y","article-title":"BNIP3L\/NIX-Mediated Mitophagy: Molecular Mechanisms and Implications for Human Disease","volume":"13","author":"Li","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ge, F., Shu, J., Liu, Z., Zhang, H., and Wang, J. (2026). Dual Roles of NIX\/BNIP3L in Tumors: Friend or Foe. Biology, 15.","DOI":"10.3390\/biology15040302"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101257","DOI":"10.1016\/j.jacbts.2025.02.016","article-title":"C-FLIP Protects Cardiac Microcirculation in Sepsis-Induced Myocardial Dysfunction Via FUNDC1-Mediated Regulation of Mitochondrial Autophagy","volume":"10","author":"Gao","year":"2025","journal-title":"JACC Basic. Transl. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR Regulate Autophagy through Direct Phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e00441-17","DOI":"10.1128\/MCB.00441-17","article-title":"MTORC1 Regulates Both General Autophagy and Mitophagy Induction after Oxidative Phosphorylation Uncoupling","volume":"37","author":"Asahara","year":"2017","journal-title":"Mol. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1083\/jcb.144.5.891","article-title":"Bid-Induced Conformational Change of Bax Is Responsible for Mitochondrial Cytochrome c Release during Apoptosis","volume":"144","author":"Desagher","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1161\/CIRCRESAHA.110.233056","article-title":"Microparticles in Hemostasis and Thrombosis","volume":"108","author":"Owens","year":"2011","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1084\/jem.20071393","article-title":"Divergent Roles of Endothelial NF-kappaB in Multiple Organ Injury and Bacterial Clearance in Mouse Models of Sepsis","volume":"205","author":"Ye","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.2147\/JIR.S504184","article-title":"The Mechanisms of Sepsis Induced Coagulation Dysfunction and Its Treatment","volume":"18","author":"Zhu","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/labinvest.3700366","article-title":"Lipopolysaccharide Signaling in Endothelial Cells","volume":"86","author":"Dauphinee","year":"2006","journal-title":"Lab. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Mar\u00ed, M., de Gregorio, E., de Dios, C., Roca-Agujetas, V., Cucarull, B., Tutusaus, A., Morales, A., and Colell, A. (2020). Mitochondrial Glutathione: Recent Insights and Role in Disease. Antioxidants, 9.","DOI":"10.3390\/antiox9100909"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/ni.1831","article-title":"Thioredoxin-Interacting Protein Links Oxidative Stress to Inflammasome Activation","volume":"11","author":"Zhou","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.immuni.2012.01.009","article-title":"Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during Apoptosis","volume":"36","author":"Shimada","year":"2012","journal-title":"Immunity"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.immuni.2013.08.001","article-title":"Mitochondrial Cardiolipin Is Required for NLRP3 Inflammasome Activation","volume":"39","author":"Iyer","year":"2013","journal-title":"Immunity"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.immuni.2019.11.005","article-title":"Bacterial Endotoxin Activates the Coagulation Cascade through Gasdermin D-Dependent Phosphatidylserine Exposure","volume":"51","author":"Yang","year":"2019","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1089\/jir.2007.0095","article-title":"Natural Killer Cells, Glutathione, Cytokines, and Innate Immunity against Mycobacterium Tuberculosis","volume":"28","author":"Millman","year":"2008","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_39","first-page":"986491","article-title":"The Role of Natural Killer Cells in Sepsis","volume":"2011","author":"Chiche","year":"2011","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Jensen, I.J., Winborn, C.S., Fosdick, M.G., Shao, P., Tremblay, M.M., Shan, Q., Tripathy, S.K., Snyder, C.M., Xue, H.-H., and Griffith, T.S. (2018). Polymicrobial Sepsis Influences NK-Cell-Mediated Immunity by Diminishing NK-Cell-Intrinsic Receptor-Mediated Effector Responses to Viral Ligands or Infections. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007405"},{"key":"ref_41","unstructured":"GEO Accession Viewer (2026, August 27). Whole Blood Transcriptome of Survivors and Nonsurvivors of Sepsis, Available online: https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=gse54514."},{"key":"ref_42","unstructured":"GEO Accession Viewer (2026, August 28). Expression Profiling Across the Pediatric Systemic Inflammatory Response Syndrome, Sepsis, And Septic Shock Spectrum, Available online: https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=gse13904."},{"key":"ref_43","unstructured":"GEO Accession Viewer (2026, August 28). Development and Validation of a Novel Molecular Biomarker Diagnostic Test for the Early Detection of Sepsis, Available online: https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE28750."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e36158","DOI":"10.7554\/eLife.36158","article-title":"Glutathione de Novo Synthesis but Not Recycling Process Coordinates with Glutamine Catabolism to Control Redox Homeostasis and Directs Murine T Cell Differentiation","volume":"7","author":"Lian","year":"2018","journal-title":"eLife"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.14336\/AD.2024.0788","article-title":"The Role of Endothelial Cell Mitophagy in Age-Related Cardiovascular Diseases","volume":"16","author":"Han","year":"2024","journal-title":"Aging Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/bja\/aer093","article-title":"Oxidative Stress and Mitochondrial Dysfunction in Sepsis","volume":"107","author":"Galley","year":"2011","journal-title":"Br. J. Anaesth."},{"key":"ref_47","first-page":"CD006616","article-title":"N-Acetylcysteine for Sepsis and Systemic Inflammatory Response in Adults","volume":"2012","author":"Szakmany","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1365-2362.1991.tb01366.x","article-title":"High-Dose Intravenous Glutathione in Man. Pharmacokinetics and Effects on Cyst(e)Ine in Plasma and Urine","volume":"21","author":"Aebi","year":"1991","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1164\/ajrccm.161.6.9903043","article-title":"The Effect of Glutathione and N-Acetylcysteine on Lipoperoxidative Damage in Patients with Early Septic Shock","volume":"161","author":"Ortolani","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e03205-22","DOI":"10.1128\/spectrum.03205-22","article-title":"Hinokitiol Selectively Enhances the Antibacterial Activity of Tetracyclines against Staphylococcus aureus","volume":"11","author":"Le","year":"2023","journal-title":"Microbiol. Spectr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1016\/j.fct.2011.04.027","article-title":"A 13-Week Subchronic Toxicity Study of Hinokitiol Administered in the Diet to F344 Rats","volume":"49","author":"Cho","year":"2011","journal-title":"Food Chem. Toxicol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.2174\/0113816128404533250915113223","article-title":"Hinokitiol as a Promising Anticancer Agent: Mechanisms of Action, Potential in Combination Therapy, and Overcoming Chemoresistance","volume":"32","author":"Ahmed","year":"2026","journal-title":"Curr. Pharm. Des."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s40560-026-00899-y","article-title":"Clinical Implications of Ferroptosis in Critical Illness: A Narrative Review","volume":"14","author":"Stroobants","year":"2026","journal-title":"J. Intensive Care"},{"key":"ref_54","first-page":"81","article-title":"The Emerging Role of Ferroptosis in the Pathological Development and Progression of Sepsis","volume":"12","author":"Zhou","year":"2025","journal-title":"Mil. Med. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1007\/s00210-023-02400-0","article-title":"Hinokitiol for Hypertensive Emergencies: Effects on Peripheral Resistance, Cardiac Load, Baroreflex Sensitivity, and Electrolytes Balance","volume":"396","author":"Omar","year":"2023","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1016\/j.jmb.2007.07.018","article-title":"Reconstitution of the Mitochondrial PrxIII Antioxidant Defence Pathway: General Properties and Factors Affecting PrxIII Activity and Oligomeric State","volume":"372","author":"Cao","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/ejcn.2017.132","article-title":"Oral Supplementation with Liposomal Glutathione Elevates Body Stores of Glutathione and Markers of Immune Function","volume":"72","author":"Sinha","year":"2018","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1001\/jama.2019.11825","article-title":"Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial","volume":"322","author":"Fowler","year":"2019","journal-title":"JAMA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.4161\/auto.6.8.13426","article-title":"p62\/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both","volume":"6","author":"Narendra","year":"2010","journal-title":"Autophagy"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/1750-1326-6-34","article-title":"Oxidation of the Cysteine-Rich Regions of Parkin Perturbs Its E3 Ligase Activity and Contributes to Protein Aggregation","volume":"6","author":"Meng","year":"2011","journal-title":"Mol. Neurodegener."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"16697","DOI":"10.1074\/jbc.M117.787739","article-title":"Reactive Oxygen Species Trigger Parkin\/PINK1 Pathway-Dependent Mitophagy by Inducing Mitochondrial Recruitment of Parkin","volume":"292","author":"Xiao","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nprot.2008.214","article-title":"Immunodesign of Experimental Sepsis by Cecal Ligation and Puncture","volume":"4","author":"Rittirsch","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.immuni.2015.02.001","article-title":"Human Monocytes Undergo Functional Re-Programming during Sepsis Mediated by Hypoxia-Inducible Factor-1\u03b1","volume":"42","author":"Shalova","year":"2015","journal-title":"Immunity"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0166-4328(01)00297-2","article-title":"Controlling the False Discovery Rate in Behavior Genetics Research","volume":"125","author":"Benjamini","year":"2001","journal-title":"Behav. Brain Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/s13059-017-1349-1","article-title":"xCell: Digitally Portraying the Tissue Cellular Heterogeneity Landscape","volume":"18","author":"Aran","year":"2017","journal-title":"Genome Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8642\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:00:39Z","timestamp":1790614839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8642"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,27]]},"references-count":65,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198642"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198642","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,27]]}}}