{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:27:44Z","timestamp":1792798064076,"version":"4.5.0"},"reference-count":39,"publisher":"IMR Press","issue":"3","license":[{"start":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T00:00:00Z","timestamp":1742342400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2023 China Medical University High-quality Development Fund","award":["2023JH2\/20200119"],"award-info":[{"award-number":["2023JH2\/20200119"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Inhibiting neuroinflammatory damage is an effective strategy for treating preterm white matter injury (PWMI). Leukemia inhibitory factor (LIF) can ameliorate (HI) induced white matter injury; however, the neuroprotective effects and mechanisms of LIF remain unclear. This study aimed to determine whether NOD-like receptor thermal protein domain associated protein (NLRP3)-dependent pyroptosis is involved in PWMI pathogenesis. Methods: We established an in vitro oxygen\u2013glucose deprivation (OGD) cell model and an in vivo HI induced brain white matter injury neonatal mouse model. RNA sequencing (RNA-seq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses examined differentially expressed genes in oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R) challenged CTX TNA2 rat astrocytes. The changes and effects of proteins were confirmed in neonatal rats in vitro and in vivo. Cell viability assays, reactive oxygen species (ROS) assays, apoptosis assays, and immunoblot were used to confirm LIF-mediated its neuroprotective effect against HI-induced white matter injury in vitro. Results: RNA-seq and KEGG analyses indicated OGD\/R enriched NLRP3 inflammasome-related genes (validated by in vitro and in vivo models), showing that NLRP3-dependent pyroptosis proteins (apoptosis-associated speck-like protein contain a CARD (ASC), NLRP3, active caspase 1, IL-1\u03b2, IL-18, and N-terminal fragment of gasdermin D (GSDMD-N)) were all increased by HI or OGD\/R. LIF upregulated HO-1 expression by activating Nrf2 via the MAPK and Akt kinase pathways and significantly decreased OGD\/R-induced ROS production. NLRP3-dependent pyroptosis proteins were suppressed in the LIF group compared with those in the OGD\/R and HI groups. Zinc protophyrin, an HO-1 inhibitor, partially abolished LIF-mediated viability enhancement in rat astrocytes. Conclusion: NLRP3-dependent pyroptosis plays a role in PWMI pathogenesis; moreover, LIF mitigates OGD\/R-induced pyroptosis-dependent neurotoxicity by upregulating HO-1 expression in rat astrocytes.<\/jats:p>","DOI":"10.31083\/fbl36630","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T12:04:10Z","timestamp":1743163450000},"source":"Crossref","is-referenced-by-count":4,"title":["Leukemia Inhibitory Factor Attenuates Hypoxic\u2013Ischemic White Matter Injury via NLRP3 Inflammasome Activity Suppressing Through the Nrf2\/HO-1 Pathway"],"prefix":"10.31083","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6711-2950","authenticated-orcid":true,"given":"Liang","family":"Huo","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Shengjing Hospital of China Medical University, 110004 Shenyang, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6419-5809","authenticated-orcid":true,"given":"Xueyan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Shengjing Hospital of China Medical University, 110004 Shenyang, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8701-0129","authenticated-orcid":true,"given":"Hua","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Shengjing Hospital of China Medical University, 110004 Shenyang, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2025,3,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Deng W, Pleasure J, Pleasure D. Progress in periventricular leukomalacia. Archives of Neurology. 2008; 65: 1291\u20131295.","DOI":"10.1001\/archneur.65.10.1291."},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Follett PL, Deng W, Dai W, Talos DM, Massillon LJ, Rosenberg PA, et al. Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate. The Journal of Neuroscience. 2004; 24: 4412\u20134420.","DOI":"10.1523\/JNEUROSCI.0477-04.2004."},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Zaghloul N, Ahmed M. Pathophysiology of periventricular leukomalacia: What we learned from animal models. Neural Regeneration Research. 2017; 12: 1795\u20131796.","DOI":"10.4103\/1673-5374.219034."},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Iida K, Takashima S, Ueda K. Immunohistochemical study of myelination and oligodendrocyte in infants with periventricular leukomalacia. Pediatric Neurology. 1995; 13: 296\u2013304.","DOI":"10.1016\/0887-8994(95)00192-1."},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Inder TE, Huppi PS, Warfield S, Kikinis R, Zientara GP, Barnes PD, et al. Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Annals of Neurology. 1999; 46: 755\u2013760. <755::aid-ana11>3.0.co;2-0.","DOI":"10.1002\/1531-8249(199911)46:5"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Paneth N, Rudelli R, Monte W, Rodriguez E, Pinto J, Kairam R, et al. White matter necrosis in very low birth weight infants: neuropathologic and ultrasonographic findings in infants surviving six days or longer. The Journal of Pediatrics. 1990; 116: 975\u2013984.","DOI":"10.1016\/s0022-3476(05)80664-x."},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Liu W, Shen Y, Plane JM, Pleasure DE, Deng W. Neuroprotective potential of erythropoietin and its derivative carbamylated erythropoietin in periventricular leukomalacia. Experimental Neurology. 2011; 230: 227\u2013239.","DOI":"10.1016\/j.expneurol.2011.04.021."},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Zaghloul N, Patel H, Ahmed MN. A model of Periventricular Leukomalacia (PVL) in neonate mice with histopathological and neurodevelopmental outcomes mimicking human PVL in neonates. PLoS ONE. 2017; 12: e0175438.","DOI":"10.1371\/journal.pone.0175438."},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Prasad JD, Gunn KC, Davidson JO, Galinsky R, Graham SE, Berry MJ, et al. Anti-Inflammatory Therapies for Treatment of Inflammation-Related Preterm Brain Injury. International Journal of Molecular Sciences. 2021; 22: 4008.","DOI":"10.3390\/ijms22084008."},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Verney C, Pogledic I, Biran V, Adle-Biassette H, Fallet-Bianco C, Gressens P. Microglial reaction in axonal crossroads is a hallmark of noncystic periventricular white matter injury in very preterm infants. Journal of Neuropathology and Experimental Neurology. 2012; 71: 251\u2013264.","DOI":"10.1097\/NEN.0b013e3182496429."},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Buch L, Lipi B, Langhnoja J, Jaldeep L, Pillai PP, Prakash P. Role of astrocytic MeCP2 in regulation of CNS myelination by affecting oligodendrocyte and neuronal physiology and axo-glial interactions. Experimental brain research. 2018; 236: 3015\u20133027.","DOI":"10.1007\/s00221-018-5363-7."},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Gearing DP, Gough NM, King JA, Hilton DJ, Nicola NA, Simpson RJ, et al. Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). The EMBO Journal. 1987; 6: 3995\u20134002.","DOI":"10.1002\/j.1460-2075.1987.tb02742.x."},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Nicola NA, Babon JJ. Leukemia inhibitory factor (LIF). Cytokine & Growth Factor Reviews. 2015; 26: 533\u2013544.","DOI":"10.1016\/j.cytogfr.2015.07.001."},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Davis SM, Reichel D, Bae Y, Pennypacker KR. Leukemia Inhibitory Factor-Loaded Nanoparticles with Enhanced Cytokine Metabolic Stability and Anti-Inflammatory Activity. Pharmaceutical Research. 2018; 35: 6.","DOI":"10.1007\/s11095-017-2282-4."},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Yang XF, Huang YX, Lan M, Zhang TR, Zhou J. Protective Effects of Leukemia Inhibitory Factor on Retinal Vasculature and Cells in Streptozotocin-induced Diabetic Mice. Chinese Medical Journal. 2018; 131: 75\u201381.","DOI":"10.4103\/0366-6999.221263."},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Han Y, Xu J, Li Z, Yang Z. Neuroprotective effect of leukemia inhibitory factor on antimycin A-induced oxidative injury in differentiated PC12 cells. Journal of Molecular Neuroscience. 2013; 50: 577\u2013585.","DOI":"10.1007\/s12031-013-0004-x."},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Sugiura S, Lahav R, Han J, Kou SY, Banner LR, de Pablo F, et al. Leukaemia inhibitory factor is required for normal inflammatory responses to injury in the peripheral and central nervous systems in vivo and is chemotactic for macrophages in vitro. The European Journal of Neuroscience. 2000; 12: 457\u2013466.","DOI":"10.1046\/j.1460-9568.2000.00922.x."},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Hendriks JJ, Slaets H, Carmans S, de Vries HE, Dijkstra CD, Stinissen P, et al. Leukemia inhibitory factor modulates production of inflammatory mediators and myelin phagocytosis by macrophages. Journal of Neuroimmunology. 2008; 204: 52\u201357.","DOI":"10.1016\/j.jneuroim.2008.07.015."},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Fischer R, Wajant H, Kontermann R, Pfizenmaier K, Maier O. Astrocyte-specific activation of TNFR2 promotes oligodendrocyte maturation by secretion of leukemia inhibitory factor. Glia. 2014; 62: 272\u2013283.","DOI":"10.1002\/glia.22605."},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Davis SM, Pennypacker KR. The role of the leukemia inhibitory factor receptor in neuroprotective signaling. Pharmacology & therapeutics. 2018; 183: 50\u201357.","DOI":"10.1016\/j.pharmthera.2017.08.008."},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Davis SM, Collier LA, Foran EA, Leonardo CC, Ajmo CT, Jr, Pennypacker KR. Neuroprotective activity of leukemia inhibitory factor is relayed through myeloid zinc finger-1 in a rat model of stroke. Metabolic Brain Disease. 2019; 34: 631\u2013640.","DOI":"10.1007\/s11011-018-0376-2."},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Davis SM, Collier LA, Leonardo CC, Seifert HA, Ajmo CT, Jr, Pennypacker KR. Leukemia Inhibitory Factor Protects Neurons from Ischemic Damage via Upregulation of Superoxide Dismutase 3. Molecular Neurobiology. 2017; 54: 608\u2013622.","DOI":"10.1007\/s12035-015-9587-2."},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Rowe DD, Collier LA, Seifert HA, Chapman CB, Leonardo CC, Willing AE, et al. Leukemia inhibitor factor promotes functional recovery and oligodendrocyte survival in rat models of focal ischemia. The European Journal of Neuroscience. 2014; 40: 3111\u20133119.","DOI":"10.1111\/ejn.12675."},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Davis SM, Collier LA, Goodwin S, Lukins DE, Powell DK, Pennypacker KR. Efficacy of leukemia inhibitory factor as a therapeutic for permanent large vessel stroke differs among aged male and female rats. Brain Research. 2019; 1707: 62\u201373.","DOI":"10.1016\/j.brainres.2018.11.017."},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Huo L, Fan Y, Wang H. Leukemia Inhibitory Factor Receptor Is Involved in Apoptosis in Rat Astrocytes Exposed to Oxygen-Glucose Deprivation. BioMed Research International. 2019; 2019: 1613820.","DOI":"10.1155\/2019\/1613820."},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Lin J, Niimi Y, Clausi MG, Kanal HD, Levison SW. Neuroregenerative and protective functions of Leukemia Inhibitory Factor in perinatal hypoxic-ischemic brain injury. Experimental Neurology. 2020; 330: 113324.","DOI":"10.1016\/j.expneurol.2020.113324."},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Mizuno K, Hida H, Masuda T, Nishino H, Togari H. Pretreatment with low doses of erythropoietin ameliorates brain damage in periventricular leukomalacia by targeting late oligodendrocyte progenitors: a rat model. Neonatology. 2008; 94: 255\u2013266.","DOI":"10.1159\/000151644."},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Qiao L, Fu J, Xue X, Shi Y, Yao L, Huang W, et al. Neuronalinjury and roles of apoptosis and autophagy in a neonatal rat model of hypoxia-ischemia-induced periventricular leukomalacia. Molecular Medicine Reports. 2018; 17: 5940\u20135949.","DOI":"10.3892\/mmr.2018.8570."},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Zhang J, Tucker LD, DongYan, Lu Y, Yang L, Wu C, et al. Tert-butylhydroquinone post-treatment attenuates neonatal hypoxic-ischemic brain damage in rats. Neurochemistry International. 2018; 116: 1\u201312.","DOI":"10.1016\/j.neuint.2018.03.004."},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Mo Y, Zhu JL, Jiang A, Zhao J, Ye L, Han B. Compound 13 activates AMPK-Nrf2 signaling to protect neuronal cells from oxygen glucose deprivation-reoxygenation. Aging. 2019; 11: 12032\u201312042.","DOI":"10.18632\/aging.102534."},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Zhai X, Lin H, Chen Y, Chen X, Shi J, Chen O, et al. Hyperbaric oxygen preconditioning ameliorates hypoxia-ischemia brain damage by activating Nrf2 expression in vivo and in vitro. Free Radical Research. 2016; 50: 454\u2013466.","DOI":"10.3109\/10715762.2015.1136411."},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Zhang M, An C, Gao Y, Leak RK, Chen J, Zhang F. Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Progress in Neurobiology. 2013; 100: 30\u201347.","DOI":"10.1016\/j.pneurobio.2012.09.003."},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Kadhim H, Khalifa M, Deltenre P, Casimir G, S\u00e9bire G. Molecular mechanisms of cell death in periventricular leukomalacia. Neurology. 2006; 67: 293\u2013299.","DOI":"10.1212\/01.wnl.0000224754.63593.c4."},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Ma DC, Zhang NN, Zhang YN, Chen HS. Salvianolic Acids for Injection alleviates cerebral ischemia\/reperfusion injury by switching M1\/M2 phenotypes and inhibiting NLRP3 inflammasome\/pyroptosis axis in microglia in vivo and in vitro. Journal of Ethnopharmacology. 2021; 270: 113776.","DOI":"10.1016\/j.jep.2021.113776."},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Xu Y, Gao X, Wang L, Yang M, Xie R. Bakuchiol ameliorates cerebral ischemia-reperfusion injury by modulating NLRP3 inflammasome and Nrf2 signaling. Respiratory Physiology & Neurobiology. 2021; 292: 103707.","DOI":"10.1016\/j.resp.2021.103707."},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Zheng WX, He WQ, Zhang QR, Jia JX, Zhao S, Wu FJ, et al. Baicalin Inhibits NLRP3 Inflammasome Activity Via the AMPK Signaling Pathway to Alleviate Cerebral Ischemia-Reperfusion Injury. Inflammation. 2021; 44: 2091\u20132105.","DOI":"10.1007\/s10753-021-01486-z."},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Zhang Y, Wang H, Li H, Nan L, Xu W, Lin Y, et al. Gualou Guizhi Granule Protects against OGD\/R-Induced Injury by Inhibiting Cell Pyroptosis via the PI3K\/Akt Signaling Pathway. Evidence-Based Complementary and Alternative Medicine. 2021; 2021: 6613572.","DOI":"10.1155\/2021\/6613572."},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Fu C, Zhang X, Lu Y, Wang F, Xu Z, Liu S, et al. Geniposide inhibits NLRP3 inflammasome activation via autophagy in BV-2 microglial cells exposed to oxygen-glucose deprivation\/reoxygenation. International Immunopharmacology. 2020; 84: 106547.","DOI":"10.1016\/j.intimp.2020.106547."},{"key":"ref39","unstructured":"Fan YY, Yu T, Zhang JM, Wang H, Zhao GF, Liu B. Expression of endogenous leukemia inhibitory factor in neonatal rats with periventricular leukomalacia. Chinese Journal of Contemporary Pediatrics. 2014; 16: 933\u2013938. (In Chinese)"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/30\/3\/10.31083\/FBL36630","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T12:13:03Z","timestamp":1743163983000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/30\/3\/10.31083\/FBL36630"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,19]]},"references-count":39,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025]]}},"alternative-id":["S2768-6701(25)01683-1"],"URL":"https:\/\/doi.org\/10.31083\/fbl36630","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,19]]},"article-number":"36630"}}