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Programmed cell death contributes to neurological damage in ischemic stroke, especially during the reperfusion stage. Several cell death pathways have been tested preclinically and clinically, including ferroptosis, necroptosis, and apoptosis. However, the sequence and complex interplay between cell death pathways during ischemia/reperfusion remains under investigation. Here, we unbiasedly investigated cell death pathways during ischemia/reperfusion by utilizing RNA sequencing analysis and immunoblot assays and revealed that ferroptosis and necroptosis occurred early post-reperfusion, followed by apoptosis. Ferroptosis inhibitor Liproxstatin-1 effectively inhibited necroptosis during reperfusion, while the necroptosis inhibitor Necrostatin-1 suppressed protein expression consistent with ferroptosis activation. Protein–protein interaction analysis and iron chelation therapy by deferoxamine mesylate indicate that iron is capable of promoting both ferroptosis and necroptosis in middle cerebral artery occlusion/repression modeled mice. Treatment of cells with iron led to a disruption in redox balance with activated necroptosis and increased susceptibility to ferroptosis. Collectively, these data uncovered a complex interplay between ferroptosis and necroptosis during ischemic stroke and indicated that multiple programmed cell death pathways may be targeted co-currently.
GBD 2016 Lifetime Risk of Stroke Collaborators, Feigin VL, Nguyen G, et al. Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016. N Engl J Med. 2018;379(25):2429-2437.
Gorelick PB. The global burden of stroke: persistent and disabling. Lancet Neurol. 2019;18(5):417-418.
Merkler AE, Parikh NS, Mir S, et al. Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza. JAMA Neurol. 2020;77(11):1-7.
Yaghi S, Ishida K, Torres J, et al. SARS-CoV-2 and stroke in a New York healthcare system. Stroke. 2020;51(7):2002-2011.
Katsanos AH, Palaiodimou L, Zand R, et al. The impact of SARS-CoV-2 on stroke epidemiology and care: a meta-analysis. Ann Neurol. 2021;89(2):380-388.
Haupt M, Gerner ST, Bähr M, Doeppner TR. Neuroprotective strategies for ischemic stroke-future perspectives. Int J Mol Sci. 2023;24(5):4334.
Shehjar F, Maktabi B, Rahman ZA, et al. Stroke: molecular mechanisms and therapies: update on recent developments. Neurochem Int. 2023;162:105458.
Fraser JF, Pahwa S, Maniskas M, et al. Now that the door is open: an update on ischemic stroke pharmacotherapeutics for the neurointerventionalist. J Neurointerv Surg. 2024;16(4):425–428.
Bai Y, Lam HC, Lei X. Dissecting programmed cell death with small molecules. Acc Chem Res. 2020;53(5):1034-1045.
Tuo QZ, Zhang ST, Lei P. Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications. Med Res Rev. 2022;42(1):259-305.
Yan HF, Tuo QZ, Yin QZ, Lei P. The pathological role of ferroptosis in ischemia/reperfusion-related injury. Zool Res. 2020;41(3):220-230.
Naito MG, Xu D, Amin P, et al. Sequential activation of necroptosis and apoptosis cooperates to mediate vascular and neural pathology in stroke. Proc Natl Acad Sci U S A. 2020;117(9):4959-4970.
Kaiser WJ, Upton JW, Long AB, et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature. 2011;471(7338):368-372.
Oberst A, Dillon CP, Weinlich R, et al. Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature. 2011;471(7338):363-367.
Tong J, Lan XT, Zhang Z, et al. Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis. Acta Pharmacol Sin. 2023;44(5):1014-1028.
Tuo QZ, Lei P, Jackman KA, et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatr. 2017;22(11):1520-1530.
Wang Q, Zhang X, Guo YJ, et al. Scopolamine causes delirium-like brain network dysfunction and reversible cognitive impairment without neuronal loss. Zool Res. 2023;44(4):712-724.
Zhang Y, Li M, Li X, et al. Catalytically inactive RIP1 and RIP3 deficiency protect against acute ischemic stroke by inhibiting necroptosis and neuroinflammation. Cell Death Dis. 2020;11(7):565.
Ritchie ME, Phipson B, Wu D, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.
Szklarczyk D, Gable AL, Lyon D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607-D613.
Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498-2504.
Weng LC, Khurshid S, Gunn S, et al. Clinical and genetic atrial fibrillation risk and discrimination of cardioembolic from noncardioembolic stroke. Stroke. 2023;54(7):1777-1785.
Jassal B, Matthews L, Viteri G, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2020;48(D1):D498-D503.
Luoqian J, Yang W, Ding X, et al. Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis. Cell Mol Immunol. 2022;19(8):913-924.
Schreiber A, Rousselle A, Becker JU, von Mässenhausen A, Linkermann A, Kettritz R. Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis. Proc Natl Acad Sci U S A. 2017;114(45):E9618-E9625.
Stark R, Grzelak M, Hadfield J. RNA sequencing: the teenage years. Nat Rev Genet. 2019;20(11):631-656.
Cho YS, Challa S, Moquin D, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009;137(6):1112-1123.
Sun L, Wang H, Wang Z, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148(1–2):213-227.
Tuo QZ, Liu Y, Xiang Z, et al. Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion. Signal Transduct Targeted Ther. 2022;7(1):59.
Chen X, Liu C, Yu R, et al. Interaction between ferroptosis and TNF-α: impact in obesity-related osteoporosis. Faseb J. 2023;37(6):e22947.
Ma H, Yan X, Liu J, Lu Y, Feng Y, Lai J. Secondary ferroptosis promotes thrombogenesis after venous injury in rats. Thromb Res. 2022;216:59-73.
Huang Y, Xu W, Zhou R. NLRP3 inflammasome activation and cell death. Cell Mol Immunol. 2021;18(9):2114-2127.
Hanson LR, Roeytenberg A, Martinez PM, et al. Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. J Pharmacol Exp Therapeut. 2009;330(3):679-686.
Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-1072.
Yan HF, Zou T, Tuo QZ, et al. Ferroptosis: mechanisms and links with diseases. Signal Transduct Targeted Ther. 2021;6(1):49.
Guo J, Tuo QZ, Lei P. Iron, ferroptosis, and ischemic stroke. J Neurochem. 2023;165(4):487-520.
Ai Y, Meng Y, Yan B, Zhou Q, Wang X. The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death. Mol Cell. 2024;84(1):170-179.
Wu Z, Geng Y, Lu X, et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc Natl Acad Sci U S A. 2019;116(8):2996-3005.
Zhang F, Li Z, Gao P, et al. HJ11 decoction restrains development of myocardial ischemia-reperfusion injury in rats by suppressing ACSL4-mediated ferroptosis. Front Pharmacol. 2022;13:1024292.
Shi L, Song Z, Li Y, et al. miR-20a-5p alleviates kidney ischemia/reperfusion injury by targeting ACSL4-dependent ferroptosis. Am J Transplant. 2023;23(1):11-25.
Tang F, Zhou LY, Li P, et al. Inhibition of ACSL4 alleviates parkinsonism phenotypes by reduction of lipid reactive oxygen species. Neurotherapeutics. 2023;20(4):1154-1166.
Li Y, Zou C, Chen C, et al. Myeloid-derived MIF drives RIPK1-mediated cerebromicrovascular endothelial cell death to exacerbate ischemic brain injury. Proc Natl Acad Sci USA. 2023;120(5):e2219091120.
Zhu YM, Lin L, Wei C, et al. The key regulator of necroptosis, RIP1 kinase, contributes to the formation of astrogliosis and glial scar in ischemic stroke. Transl Stroke Res. 2021;12(6):991-1017.
Degterev A, Ofengeim D, Yuan J. Targeting RIPK1 for the treatment of human diseases. Proc Natl Acad Sci U S A. 2019;116(20):9714-9722.
Gupta R, Kumari S, Tripathi R, Ambasta RK, Kumar P. Unwinding the modalities of necrosome activation and necroptosis machinery in neurological diseases. Ageing Res Rev. 2023;86:101855.
Deng XX, Li SS, Sun FY. Necrostatin-1 prevents necroptosis in brains after ischemic stroke via inhibition of RIPK1-mediated RIPK3/MLKL signaling. Aging Dis. 2019;10(4):807-817.
Degterev A, Hitomi J, Germscheid M, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4(5):313-321.
Tian J, Guo S, Chen H, et al. Combination of emricasan with ponatinib synergistically reduces ischemia/reperfusion injury in rat brain through simultaneous prevention of apoptosis and necroptosis. Transl Stroke Res. 2018;9(4):382-392.
Yuk H, Abdullah M, Kim DH, Lee H, Lee SJ. Necrostatin-1 prevents ferroptosis in a RIPK1- and Ido-independent manner in hepatocellular carcinoma. Antioxidants. 2021;10(9):1347.
Lamade AM, Wu L, Dar HH, et al. Inactivation of RIP3 kinase sensitizes to 15LOX/PEBP1-mediated ferroptotic death. Redox Biol. 2022;50:102232.
Ö Canli, Alankuş YB, Grootjans S, et al. Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors. Blood. 2016;127(1):139-148.
Peng C, Zhao F, Li H, Li L, Yang Y, Liu F. HSP90 mediates the connection of multiple programmed cell death in diseases. Cell Death Dis. 2022;13(11):929.
Ros U, Peña-Blanco A, Hänggi K, et al. Necroptosis execution is mediated by plasma membrane nanopores independent of calcium. Cell Rep. 2017;19(1):175-187.
Ushijima H, Monzaki R. An in vitro evaluation of the antioxidant activities of necroptosis and apoptosis inhibitors: the potential of necrostatin-1 and necrostatin-1i to have radical scavenging activities. Pharmacol Rep. 2023;75(2):490-497.
Tian Q, Qin B, Gu Y, et al. ROS-mediated necroptosis is involved in iron overload-induced osteoblastic cell death. Oxid Med Cell Longev. 2020;2020:1295382.
Chen X, Yu C, Kang R, Tang D. Iron metabolism in ferroptosis. Front Cell Dev Biol. 2020;8:590226.
Lei P, Ayton S, Finkelstein DI, et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med. 2012;18(2):291-295.
Guo YJ, Xiong H, Chen K, Zou JJ, Lei P. Brain regions susceptible to alpha-synuclein spreading. Mol Psychiatr. 2022;27(1):758-770.
Wang P, Zheng SY, Jiang RL, et al. Necroptosis signaling and mitochondrial dysfunction cross-talking facilitate cell death mediated by chelerythrine in glioma. Free Radic Biol Med. 2023;202:76-96.
Jiao L, Li X, Luo Y, et al. Iron metabolism mediates microglia susceptibility in ferroptosis. Front Cell Neurosci. 2022;16:995084.
Lee BWL, Ghode P, Ong DST. Redox regulation of cell state and fate. Redox Biol. 2019;25:101056.
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