Histone lactylation exacerbates acute lung injury in septic mice by promoting ferroptosis in pulmonary microvascular endothelial cells

Abstract

Background: Circulating lactate is associated with poor prognosis in sepsis-induced acute lung injury (S-ALI). However, it remains unclear whether microvascular dysfunction, a hallmark of S-ALI, is related to circulating lactate levels and what the underlying mechanisms are. The aim of this study was to investigate the role and mechanisms of lactate in pulmonary microvascular dysfunction in S-ALI. Methods: The effects of lactate on pulmonary microvascular function were assessed in a septic mouse model. Primary mouse pulmonary microvascular endothelial cells (MPMVECs) were isolated to evaluate the impact of lactate on MPMVEC permeability. Transcriptomic sequencing was employed to investigate the involvement of lactate in regulating MPMVEC ferroptosis, and the results were validated by in vivo and in vitro experiments. Histone lactylation was identified as a regulator of lipid peroxidation and iron homeostasis dysregulation in lactate-induced ferroptosis in MPMVECs. Gain-and loss-of-function approaches were used to assess the role of histone lactylation in regulating ferroptosis and pulmonary microvascular dysfunction. Correlations between serum lactate and ferroptosis levels and their associations with patient prognosis were investigated in patients with sepsis-associated acute respiratory distress syndrome (S-ARDS). Results: The mouse serum lactate level reached a peak at 18 h after caecal ligation and puncture surgery. Elevated lactate levels during sepsis promoted ferroptosis in PMVECs, leading to increased pulmonary vascular permeability and exacerbation of ALI. Mechanistically, lactate increased the lactylation of histone H3 at K18 (H3K18la), which promoted ACSL4 transcription in MPMVECs, resulting in excessive lipid peroxidation. Additionally, elevated H3K18la promoted LC3 transcription and indirectly upregulated NCOA4 expression through the transcription factor GATA2, facilitating ferritinophagy. Serum lactate levels were significantly correlated with ferroptosis levels in S-ARDS patients, and both were associated with poor patient prognosis. Conclusions: This study revealed a critical role for high lactate-derived histone lactylation in PMVEC ferroptosis and the progression of ALI during sepsis, providing new insights and potential therapeutic mechanisms.

Keywords

Sepsis-induced acute lung injury / Histone lactylation / Ferroptosis / Lipid peroxidation / Ferritinophagy

References

[1] Wu M, Mi B, Liu L, Ma H, Jiang C, Jiang S, et al. Genetic polymorphisms, biomarkers and signaling pathways associated with septic shock: from diagnosis to therapeutic targets. Burns Trauma 2024; 12: tkae006. https://doi.org/10.1093/burnst/tkae006.

[2] McMullan RR, McAuley DF, O’Kane CM, Silversides JA. Vascular leak in sepsis: physiological basis and potential therapeutic advances. Crit Care 2024; 28: 97. https://doi.org/10.1186/s13054-024-04875-6.

[3] Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the global burden of disease study. Lancet 2020; 395: 200-11. https://doi.org/10.1016/S0140-6736(19)32989-7.

[4] Xie J, Wang H, Kang Y, Zhou L, Liu Z, Qin B, et al. The epidemiology of sepsis in Chinese ICUs: a national cross-sectional survey. Crit Care Med 2020; 48: e209-18. https://doi.org/10.1097/CCM.0000000000004155.

[5] Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012; 122: 2731-40. https://doi.org/10.1172/JCI60331.

[6] Cai W, Shen K, Ji P, Jia Y, Han S, Zhang W, et al. The Notch pathway attenuates burn-induced acute lung injury in rats by repressing reactive oxygen species. Burns Trauma 2022; 10: tkac008. https://doi.org/10.1093/burnst/tkac008.

[7] Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149: 1060-72. https://doi.org/10.1016/j.cell.2012.03.042.

[8] Dai E, Chen X, Linkermann A, Jiang X, Kang R, Kagan VE, et al. A guideline on the molecular ecosystem regulating ferroptosis. Nat Cell Biol 2024; 26: 1447-57. https://doi.org/10.1038/s41556-024-01360-8.

[9] Bai T, Li M, Liu Y, Qiao Z, Wang Z. Inhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell. Free Radic Biol Med 2020; 160: 92-102. https://doi.org/10.1016/j.freeradbiomed.2020.07.026.

[10] Wen Z, Fan J, Zhan F, Li X, Li B, Lu P, et al. The role of FPR2-mediated ferroptosis in formyl peptide-induced acute lung injury against endothelial barrier damage and protective effect of the mitochondria-derived peptide MOTS-c. Int Immunopharmacol 2024; 131: 111911. https://doi.org/10.1016/j.intimp.2024.111911.

[11] Zhang H, Zhou S, Sun M, Hua M, Liu Z, Mu G, et al. Ferroptosis of endothelial cells in vascular diseases. Nutrients 2022; 14: 4506. https://doi.org/10.3390/nu14214506.

[12] Wang W, Xu R, He P, Xiong Y, Zhao H, Fu X, et al. CircEXOC5 aggravates sepsis-induced acute lung injury by promoting ferroptosis through the IGF2BP2/ATF3 Axis. J Infect Dis 2024; 229: 522-34. https://doi.org/10.1093/infdis/jiad337.

[13] Fei Y, Huang X, Ning F, Qian T, Cui J, Wang X, et al. NETs induce ferroptosis of endothelial cells in LPS-ALI through SDC-1/HS and downstream pathways. Biomed Pharmacother 2024; 175: 116621. https://doi.org/10.1016/j.biopha.2024.116621.

[14] Shen K, Wang X, Wang Y, Jia Y, Zhang Y, Wang K, et al. miR-125b-5p in adipose derived stem cells exosome alleviates pulmonary microvascular endothelial cells ferroptosis via Keap1/Nrf2/GPX4 in sepsis lung injury. Redox Biol 2023; 62: 102655. https://doi.org/10.1016/j.redox.2023.102655.

[15] Vandewalle J, Libert C. Sepsis: a failing starvation response. Trends Endocrinol Metab 2022; 33: 292-304. https://doi.org/10.1016/j.tem.2022.01.006.

[16] Träger K, DeBacker D, Radermacher P. Metabolic alterations in sepsis and vasoactive drug-related metabolic effects. Curr Opin Crit Care 2003; 9: 271-8. https://doi.org/10.1097/00075198-200308000-00004.

[17] Mookerjee SA, Gerencser AA, Nicholls DG, Brand MD. Quantifying intracellular rates of glycolytic and oxidative ATP production and consumption using extracellular flux measurements. J Biol Chem 2017; 292: 7189-207. https://doi.org/10.1074/jbc.M116.774471.

[18] Kotani Y, Ryan N, Udy AA, Fujii T. Haemodynamic management of septic shock. Burns Trauma 2025; 13: tkae081. https://doi.org/10.1093/burnst/tkae081.

[19] Oh DH, Kim MH, Jeong WY, Kim YC, Kim EJ, Song JE, et al. Risk factors for mortality in patients with low lactate level and septic shock. J Microbiol Immunol Infect 2019; 52: 418-25. https://doi.org/10.1016/j.jmii.2017.08.009.

[20] Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. Int J Mol Sci 2019; 20: 5376. https://doi.org/10.3390/ijms20215376.

[21] Sun Z, Song Y, Li J, Li Y, Yu Y, Wang X. Potential biomarker for diagnosis and therapy of sepsis: lactylation. Immun Inflamm Dis 2023; 11: e1042. https://doi.org/10.1002/iid3.1042.

[22] Yang K, Fan M, Wang X, Xu J, Wang Y, Gill PS, et al. Lactate induces vascular permeability via disruption of VE-cadherin in endothelial cells during sepsis. Sci Adv 2022; 8: eabm8965. https://doi.org/10.1126/sciadv.abm8965.

[23] Wang Z, Zhao F, Xu C, Zhang Q, Ren H, Huang X, et al. Metabolic reprogramming in skin wound healing. Burns Trauma 2024; 12: tkad047. https://doi.org/10.1093/burnst/tkad047.

[24] Zhao Y, Chen Z, Xie S, Xiao F, Hu Q, Ju Z. The emerging role and therapeutical implications of ferroptosis in wound healing. Burns Trauma 2025; 13: tkae082. https://doi.org/10.1093/burnst/tkae082.

[25] Yang Z, Su W, Wei X, Qu S, Zhao D, Zhou J, et al. HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1. Cell Rep 2023; 42: 112945. https://doi.org/10.1016/j.celrep.2023.112945.

[26] Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature 2019; 574: 575-80. https://doi.org/10.1038/s41586-019-1678-1.

[27] Chu X, Di C, Chang P, Li L, Feng Z, Xiao S, et al. Lactylated histone H3K18 as a potential biomarker for the diagnosis and predicting the severity of septic shock. Front Immunol 2022; 12: 786666. https://doi.org/10.3389/fimmu.2021.786666.

[28] Ang K, Fan M, Wang X, Xu J, Wang Y, Tu F, et al. Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis. Cell Death Differ 2022; 29: 133-46. https://doi.org/10.1038/s41418-021-00841-9.

[29] An S, Yao Y, Hu H, Wu J, Li J, Li L, et al. PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation. Cell Death Dis 2023; 14: 457. https://doi.org/10.1038/s41419-023-05952-4.

[30] Wright SW, Hantrakun V, Rudd KE, Lau CY, Lie KC, Chau NVV, et al. Enhanced bedside mortality prediction combining point-of-care lactate and the quick Sequential Organ Failure Assessment (qSOFA) score in patients hospitalised with suspected infection in Southeast Asia: a cohort study. Lancet Glob Health 2022; 10: e1281-8. https://doi.org/10.1016/S2214-109X(22)00277-7.

[31] Hargreaves DS, de Carvalho JLJ, Smith L, Picton G, Venn R, Hodgson LE. Persistently elevated early warning scores and lactate identifies patients at high risk of mortality in suspected sepsis. Eur J Emerg Med 2020; 27: 125-31. https://doi.org/10.1097/MEJ.0000000000000630.

[32] Mauri T, Spinelli E, Pavlovsky B, Grieco DL, Ottaviani I, Basile MC, et al. Respiratory drive in patients with sepsis and septic shock: modulation by high-flow nasal cannula. Anesthesiology 2021; 135: 1066-75. https://doi.org/10.1097/ALN.0000000000004010.

[33] Epstein T, Gatenby RA, Brown JS. The Warburg effect as an adaptation of cancer cells to rapid fluctuations in energy demand. PLoS One 2017; 12: e0185085. https://doi.org/10.1371/journal.pone.0185085.

[34] Zheng Z, Ma H, Zhang X, Tu F, Wang X, Ha T, et al. Enhanced glycolytic metabolism contributes to cardiac dysfunction in polymicrobial sepsis. J Infect Dis 2017; 215: 1396-406. https://doi.org/10.1093/infdis/jix138.

[35] Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity 2014; 40: 463-75. https://doi.org/10.1016/j.immuni.2014.04.001.

[36] Gao M, Yu T, Liu D, Shi Y, Yang P, Zhang J, et al. Sepsis plasma-derived exosomal miR-1-3p induces endothelial cell dysfunction by targeting SERP1. Clin Sci (Lond) 2021; 135: 347-65. https://doi.org/10.1042/CS20200573.

[37] Lu Z, Fang P, Li S, Xia D, Zhang J, Wu X, et al. Lactylation of Histone H3k18 and Egr1 Promotes Endothelial Glycocalyx Degradation in Sepsis-Induced Acute Lung Injury. Adv Sci (Weinh) 2024; 92: 110250. https://doi.org/10.1002/advs.202407064.

[38] Xia D, Lu Z, Li S, Fang P, Yang C, He X, et al. Development of an intelligent reactive oxygen species-responsive dual-drug delivery nanoplatform for enhanced precise therapy of acute lung injury. Int J Nanomedicine 2024; 19: 2179-97. https://doi.org/10.2147/IJN.S442727.

[39] Wang Y, Kuang X, Yin Y, Han N, Chang L, Wang H, et al. Tongxinluo prevents chronic obstructive pulmonary disease complicated with atherosclerosis by inhibiting ferroptosis and protecting against pulmonary microvascular barrier dysfunction. Biomed Pharmacother 2022; 145: 112367. https://doi.org/10.1016/j.biopha.2021.112367.

[40] Wu D, Spencer CB, Ortoga L, Zhang H, Miao C. Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury. Redox Biol 2024; 74: 103194. https://doi.org/10.1016/j.redox.2024.103194.

[41] Chen F, Kang R, Tang D, Liu J. Ferroptosis: principles and significance in health and disease. J Hematol Oncol 2024; 17: 41. https://doi.org/10.1186/s13045-024-01564-3.

[42] Conrad M, Pratt DA. The chemical basis of ferroptosis. Nat Chem Biol 2019; 15: 1137-47. https://doi.org/10.1038/s41589-019-0408-1.

[43] Stockwell BR. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell 2022; 185: 2401-21. https://doi.org/10.1016/j.cell.2022.06.003.

[44] Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, et al. Ferroptosis: past, present and future. Cell Death Dis 2020; 11: 88. https://doi.org/10.1038/s41419-020-2298-2.

[45] Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol 2016; 26: 165-76. https://doi.org/10.1016/j.tcb.2015.10.014.

[46] Dalleau S, Baradat M, Guéraud F, Huc L. Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance. Cell Death Differ 2013; 20: 1615-30. https://doi.org/10.1038/cdd.2013.138.

[47] Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 2017; 13: 91-8. https://doi.org/10.1038/nchembio.2239.

[48] Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 2017; 13: 81-90. https://doi.org/10.1038/nchembio.2238.

[49] Gozzelino R, Arosio P. Iron homeostasis in health and disease. Int J Mol Sci 2016; 17: 130. https://doi.org/10.3390/ijms17010130.

[50] Wu H, Liu Q, Shan X, Gao W, Chen Q. ATM orchestrates ferritinophagy and ferroptosis by phosphorylating NCOA4. Autophagy 2023; 19: 2062-77. https://doi.org/10.1080/15548627.2023.2170960.

[51] Murphy BM, O’Neill AJ, Adrain C, Watson RW, Martin SJ. The apoptosome pathway to caspase activation in primary human neutrophils exhibits dramatically reduced requirements for cytochrome C. J Exp Med 2003; 197: 625-32. https://doi.org/10.1084/jem.20021862.

[52] Schwartz AL, Ciechanover A. Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu Rev Pharmacol Toxicol 2009; 49: 73-96. https://doi.org/10.1146/annurev.pharmtox.051208.165340.

[53] Ma Z, Bai J, Jiang C, Zhu H, Liu D, Pan M, et al. Tegument protein UL21 of alpha-herpesvirus inhibits the innate immunity by triggering CGAS degradation through TOLLIP-mediated selective autophagy. Autophagy 2023; 19: 1512-32. https://doi.org/10.1080/15548627.2022.2139921.

[54] Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 2014; 509: 105-9. https://doi.org/10.1038/nature13148.

[55] Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 2016; 12: 1425-8. https://doi.org/10.1080/15548627.2016.1187366.

[56] Chen X, Yu C, Kang R, Kroemer G, Tang D. Cellular degradation systems in ferroptosis. Cell Death Differ 2021; 28: 1135-48. https://doi.org/10.1038/s41418-020-00728-1.

[57] Xie Y, Hu H, Liu M, Zhou T, Cheng X, Huang W, et al. The role and mechanism of histone lactylation in health and diseases. Front Genet 2022; 13: 949252. https://doi.org/10.3389/fgene.2022.949252.

[58] Lu Z, Zheng X, Shi M, Yin Y, Liang Y, Zou Z, et al. Lactylation: the emerging frontier in post-translational modification. Front Genet 2024; 15: 1423213. https://doi.org/10.3389/fgene.2024.1423213.

[59] Liu J, Wang Y, Zeng L, Yu C, Kang R, Klionsky DJ, et al. Extracellular NCOA4 is a mediator of septic death by activating the AGER-NFKB pathway. Autophagy 2024; 20: 2616-31. https://doi.org/10.1080/15548627.2024.2372215.

[60] Liu S, Yang T, Jiang Q, Zhang L, Shi X, Liu X, et al. Lactate and lactylation in sepsis: a comprehensive review. J Inflamm Res 2024; 17: 4405-17. https://doi.org/10.2147/JIR.S459185.

[61] Suetrong B, Walley KR. Lactic acidosis in sepsis: it’s not all anaerobic: implications for diagnosis and management. Chest 2016; 149: 252-61. https://doi.org/10.1378/chest.15-1703.

[62] Wautier JL, Wautier MP. Vascular permeability in diseases. Int J Mol Sci 2022; 23: 3645. https://doi.org/10.3390/ijms23073645.

[63] Wakasugi R, Suzuki K, Kaneko-Kawano T. Molecular mechanisms regulating vascular endothelial permeability. Int J Mol Sci 2024; 25: 6415. https://doi.org/10.3390/ijms25126415.

[64] Bayır H, Dixon SJ, Tyurina YY, Kellum JA, Kagan VE. Ferroptotic mechanisms and therapeutic targeting of iron metabolism and lipid peroxidation in the kidney. Nat Rev Nephrol 2023; 19: 315-36. https://doi.org/10.1038/s41581-023-00689-x.

[65] Huo L, Liu C, Yuan Y, Liu X, Cao Q. Pharmacological inhibition of ferroptosis as a therapeutic target for sepsis-associated organ damage. Eur J Med Chem 2023; 257: 115438. https://doi.org/10.1016/j.ejmech.2023.115438.

[66] Wei XB, Jiang WQ, Zeng JH, Huang LQ, Ding HG, Jing YW, et al. Exosome-derived lncRNA NEAT1 exacerbates sepsis-associated encephalopathy by promoting ferroptosis through regulating miR-9-5p/TFRC and GOT1 axis. Mol Neurobiol 2022; 59: 1954-69. https://doi.org/10.1007/s12035-022-02738-1.

[67] Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA 2016; 113: E4966-75. https://doi.org/10.1073/pnas.1603244113.

[68] Golej DL, Askari B, Kramer F, Barnhart S, Vivekanandan-Giri A, Pennathur S, et al. Long-chain acyl-CoA synthetase 4 modulates prostaglandin E2 release from human arterial smooth muscle cells. J Lipid Res 2011; 52: 782-93. https://doi.org/10.1194/jlr.M013292.

[69] Klett EL, Chen S, Edin ML, Li LO, Ilkayeva O, Zeldin DC, et al. Diminished acyl-CoA synthetase isoform 4 activity in INS 832/13 cells reduces cellular epoxyeicosatrienoic acid levels and results in impaired glucose-stimulated insulin secretion. J Biol Chem 2013; 288: 21618-29. https://doi.org/10.1074/jbc.M113.481077.

[70] Shimbara-Matsubayashi S, Kuwata H, Tanaka N, Kato M, Hara S. Analysis on the substrate specificity of recombinant human acyl-CoA synthetase ACSL4 variants. Biol Pharm Bull 2019; 42: 850-5. https://doi.org/10.1248/bpb.b19-00085.

[71] Gijón MA, Riekhof WR, Zarini S, Murphy RC, Voelker DR. Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. J Biol Chem 2008; 283: 30235-45. https://doi.org/10.1074/jbc.M806194200.

[72] Gan B.ACSL4, PUFA, and ferroptosis: new arsenal in anti-tumor immunity. Signal Transduct Target Ther 2022; 7: 128. https://doi.org/10.1038/s41392-022-01004-z.

[73] Kan CF, Singh AB, Stafforini DM, Azhar S, Liu J. Arachidonic acid downregulates acyl-CoA synthetase 4 expression by promoting its ubiquitination and proteasomal degradation. J Lipid Res 2014; 55: 1657-67. https://doi.org/10.1194/jlr.M045971.

[74] Dong M, Zhang Y, Chen M, Tan Y, Min J, He X, et al. ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT. Acta Pharm Sin B 2024; 14: 3027-48. https://doi.org/10.1016/j.apsb.2024.03.008.

[75] Sun W, Jia M, Feng Y, Cheng X. Lactate is a bridge linking glycolysis and autophagy through lactylation. Autophagy 2023; 19: 3240-1. https://doi.org/10.1080/15548627.2023.2246356.

[76] Jia M, Yue X, Sun W, Zhou Q, Chang C, Gong W, et al. ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation. Sci Adv 2023; 9: eadg4993. https://doi.org/10.1126/sciadv.adg4993.

[77] Zhang Y, Huang Z, Han W, Wu J, Li S, Qin T, et al. Glutamine suppresses senescence and promotes autophagy through glycolysis inhibition-mediated AMPKα lactylation in intervertebral disc degeneration. Commun Biol 2024; 7: 325. https://doi.org/10.1038/s42003-024-06000-3.

[78] Bresnick EH, Johnson KD. Blood disease-causing and-suppressing transcriptional enhancers: general principles and GATA2 mechanisms. Blood Adv 2019; 3: 2045-56. https://doi.org/10.1182/bloodadvances.2019000378.

[79] Huang D, Chen D, Hu T, Liang H. GATA2 promotes oxidative stress to aggravate renal ischemia-reperfusion injury by upregulating Redd1. Mol Immunol 2023; 153: 75-84. https://doi.org/10.1016/j.molimm.2022.09.012.

[80] Yu L, Moriguchi T, Kaneko H, Hayashi M, Hasegawa A, Nezu M, et al. Reducing inflammatory cytokine production from renal collecting duct cells by inhibiting GATA2 ameliorates acute kidney injury. Mol Cell Biol 2017; 37: e00211-7. https://doi.org/10.1128/MCB.00211-17.

[81] Hu Y, He Z, Li Z, Wang Y, Wu N, Sun H, et al. Lactylation: the novel histone modification influence on gene expression, protein function, and disease. Clin Epigenetics 2024; 16: 72. https://doi.org/10.1186/s13148-024-01682-2.

[82] He X, Wang Z, Ge Q, Sun S, Li R, Wang B. Lactylation of nuclear receptor coactivator 4 promotes ferritinophagy and glycolysis of neuronal cells after cerebral ischemic injury. Neuroreport 2024; 35: 895-903. https://doi.org/10.1097/WNR.0000000000002080.

[83] Wu D, Sunkel B, Chen Z, Liu X, Ye Z, Li Q, et al. Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer. Nucleic Acids Res 2014; 42: 3607-22. https://doi.org/10.1093/nar/gkt1382.