{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:48:57Z","timestamp":1792183737609,"version":"4.4.0"},"reference-count":57,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32573448"],"award-info":[{"award-number":["32573448"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32573448"],"award-info":[{"award-number":["32573448"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"crossref","award":["LH2023C206"],"award-info":[{"award-number":["LH2023C206"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The link between neutrophil extracellular traps (NETs) and hepatocyte ferroptosis in liver ischemia\u2013reperfusion injury (LIRI) is unclear. Adipose-derived mesenchymal stem cell exosomes (ADSCs-Exo) hold therapeutic potential for LIRI. This study employed miniature pigs to investigate the NETs\u2019 role and ADSCs-Exo\u2019s protection in LIRI. In vitro, established hepatocyte oxygen-glucose deprivation\/reoxygenation (OGD\/R) model and Transwell co-culture system with polymorphonuclear neutrophils (PMNs). In vivo, a laparoscopic minimally invasive LIRI model was constructed in miniature pigs, followed by ADSCs-Exo intervention. Results demonstrated that NETs exacerbate OGD\/R-induced hepatocyte ferroptosis via myeloperoxidase. ADSCs-Exo inhibited NET formation via the NADPH\/MAPK pathway, thereby mitigating ferroptosis, and ultimately improved liver histopathology and function. This study is the first to demonstrate in a large animal model that ADSCs-Exo alleviate LIRI by inhibiting NET formation via the NADPH\/MAPK pathway, consequently attenuating hepatocyte ferroptosis. These findings provide novel insights into LIRI pathogenesis, support the translational potential of ADSCs-Exo as a cell-free therapeutic strategy, and highlight the value of the miniature pig model in liver research.<\/jats:p>","DOI":"10.3390\/cells15111040","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T14:10:42Z","timestamp":1780668642000},"page":"1040","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ADSCs-Exo Attenuate NET Formation via the NADPH\/MAPK Pathway and Mitigate NETs-Mediated Exacerbation of Hepatocyte Ferroptosis in a Miniature Pig Model of LIRI"],"prefix":"10.3390","volume":"15","author":[{"given":"Xiangyu","family":"Lu","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"},{"name":"Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pujun","family":"Li","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"},{"name":"Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Cao","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"},{"name":"Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"},{"name":"Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajun","family":"Ma","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"},{"name":"Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Piao","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"},{"name":"Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4454-3328","authenticated-orcid":false,"given":"Hongbin","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"},{"name":"Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3727\/105221617X15042750874156","article-title":"Hepatic Ischemia\/Reperfusion: Mechanisms of Tissue Injury, Repair, and Regeneration","volume":"17","author":"Konishi","year":"2017","journal-title":"Gene Expr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101465","DOI":"10.1016\/j.gendis.2024.101465","article-title":"Multi-time point transcriptomics and metabolomics reveal key transcription and metabolic features of hepatic ischemia-reperfusion injury in mice","volume":"12","author":"Li","year":"2025","journal-title":"Genes Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.2174\/138161206777947614","article-title":"Oxidative stress in hepatic ischemia-reperfusion injury: The role of antioxidants and iron chelating compounds","volume":"12","author":"Galaris","year":"2006","journal-title":"Curr. 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