Advances in Mechanisms of Neuronal Death After Subarachnoid Hemorrhage

doi:10.3870/j.issn.1672-8009.2026.01.012

Abstract

Abstract: Subarachnoid hemorrhage(SAH)is a critical neurological emergency.The mechanisms of brain injury following SAH are complex and multifaceted,with neuronal death serving as a pivotal pathological process.This article reviews recent researches on neuronal death mechanisms following SAH,covering apoptosis,pyroptosis,autophagy,necroptosis,ferroptosis,and other pathways.It also preliminarily explores relevant intervention strategies,aiming to provide new insights for the clinical management of SAH.

Key words: subarachnoid hemorrhage, neuronal death, mechanisms

CLC Number:

R743.35

WANG Hai, SUN Xingang. Advances in Mechanisms of Neuronal Death After Subarachnoid Hemorrhage[J]. Journal of Medical Molecular Biology, 2026, 23(1): 85-89.

References

[1] TIAN Q,LIU S,HAN S M,et al.The mechanism and relevant mediators associated with neuronal apoptosis and potential therapeutic targets in subarachnoid hemorrhage[J].Neural Regen Res,2023,18(2):244-252.
[2] YAN C,YU H,LIU Y,et al.C-abl tyrosine kinase-mediated neuronal apoptosis in subarachnoid hemorrhage by modulating the LRP-1-dependent Akt/GSK3β survival pathway[J].J Mol Neurosci,2021,71(12):2514-2525.
[3] ZHANG T,ZHANG M.NL-1 promotes PINK1-parkin-mediated mitophagy through MitoNEET inhibition in subarachnoid hemorrhage[J].Neurochem Res,2024,49(6):1506-1516.
[4] TIAN Q,LIU C,LIAO J,et al.ATF2/BAP1 axis mediates neuronal apoptosis after subarachnoid hemorrhage via P53 pathway[J].Stroke,2024,55(8):2113-2125.
[5] YANG J,WU Q,LAN S,et al.Peroxiredoxin-5 alleviates early brain injury after subarachnoid hemorrhage by reducing oxidative stress[J].Brain Res Bull,2024,217:111087.
[6] HAN Y,HAO G,HAN S,et al.Polydatin ameliorates early brain injury after subarachnoid hemorrhage through up-regulating SIRT1 to suppress endoplasmic reticulum stress[J].Front Pharmacol,2024,15:1450238.
[7] SHI H,FANG Y,HUANG L,et al.Activation of galanin receptor 1 with M617 attenuates neuronal apoptosis via ERK/GSK-3β/TIP60 pathway after subarachnoid hemorrhage in rats[J].Neurotherapeutics,2021,18(3):1905-1921.
[8] LUO X,LI L,XU W,et al.HLY78 attenuates neuronal apoptosis via the LRP6/GSK3β/β-catenin signaling pathway after subarachnoid hemorrhage in rats[J].Neurosci Bull,2020,36(10):1171-1181.
[9] CHENG W,WEI B,LIU W,et al.p97 inhibits integrated stress response-induced neuronal apoptosis after subarachnoid hemorrhage in mice by enhancing proteasome function[J].Exp Neurol,2024,377:114778.
[10] WU H,YU N,WANG X,et al.Tauroursodeoxycholic acid attenuates neuronal apoptosis via the TGR5/SIRT3 pathway after subarachnoid hemorrhage in rats[J].Biol Res,2020,53(1):56.
[11] WU Q,YUAN K,YAO Y,et al.LAMC1 attenuates neuronal apoptosis via FAK/PI3K/AKT signaling pathway after subarachnoid hemorrhage[J].Exp Neurol,2024,376:114776.
[12] DING P F,LIU X Z,PENG Z,et al.miR-93-5p impairs autophagy-lysosomal pathway via TET3 after subarachnoid hemorrhage[J].Exp Neurol,2024,380:114904.
[13] HE W,ZHOU X,WU Q,et al.Acetyl CoA synthase 2 potentiates ATG5-induced autophagy against neuronal apoptosis after subarachnoid hemorrhage[J].J Mol Histol,2022,53(2):511-521.
[14] LI Z Y,YANG X,WANG J K,et al.MFGE8 promotes adult hippocampal neurogenesis in rats following experimental subarachnoid hemorrhage via modifying the integrin β3/Akt signaling pathway[J].Cell Death Discov,2024,10(1):359.
[15] ZOU L,XU S,WANG C,et al.Methylated MFGE8 promotes early brain injury after subarachnoid hemorrhage and inhibiting autophagy of nerve cell[J].Transl Stroke Res,2025,16(2):350-367.
[16] ZENG H,CHEN H,LI M,et al.Autophagy protein NRBF2 attenuates endoplasmic reticulum stress-associated neuroinflammation and oxidative stress via promoting autophagosome maturation by interacting with Rab7 after SAH[J].J Neuroinflammation,2021,18(1):210.
[17] CHANG H,LIN C,LI Z,et al.T3 alleviates neuroinflammation and reduces early brain injury after subarachnoid haemorrhage by promoting mitophagy via PINK 1-parkin pathway[J].Exp Neurol,2022,357:114175.
[18] CHEN J,ZHANG C,YAN T,et al.Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of pyroptosis and neuroinflammation[J].J Cell Physiol,2021,236(10):6920-6931.
[19] ZHOU K,ENKHJARGAL B,MO J,et al.Dihydrolipoic acid enhances autophagy and alleviates neurological deficits after subarachnoid hemorrhage in rats[J].Exp Neurol,2021,342:113752.
[20] ZOU Y,TAO Z X,LI P P,et al.Clemastine attenuates subarachnoid haemorrhage pathology in a mouse model via Nrf2/SQSTM1-mediated autophagy[J].Br J Pharmacol,2025,182(12):2730-2753.
[21] YANG Y,ZHANG J,DU Y.miR-30c-5p protects from brain injury after cerebral aneurysmal subarachnoid hemorrhage through the ATG5/ATG12 pathway[J].Altern Ther Health Med,2024,30(11):AT9813.
[22] HU X,ZHU Y,ZHOU F,et al.Efficacy of melatonin in animal models of subarachnoid hemorrhage:A systematic review and stratified meta-analysis[J].Front Neurol,2021,12:685731.
[23] CAI W,WU Q,YAN Z Z,et al.Neuroprotective effect of ultrasound triggered astaxanthin release nanoparticles on early brain injury after subarachnoid hemorrhage[J].Front Chem,2021,9:775274.
[24] XIE Z Y,XU Y X,YAO L.Angiotensin II can trigger HSC-LX2 pyroptosis through both classical and non-classical pathways[J].Life Sci,2022,307:120878.
[25] LUO K,YANG L,LIU Y,et al.HDAC inhibitor SAHA alleviates pyroptosis by up-regulating miR-340 to inhibit NEK7 signaling in subarachnoid hemorrhage[J].Neurochem Res,2023,48(2):458-470.
[26] TANG S,LAI N,XU L.Neuronal pyroptosis mediated by STAT3 in early brain injury after subarachnoid hemorrhage[J].Brain Res,2024,1822:148666.
[27] CAI W,WU Z,LAI J,et al.LDC7559 inhibits microglial activation and GSDMD-dependent pyroptosis after subarachnoid hemorrhage[J].Front Immunol,2023,14:1117310.
[28] DING M,JIN L,WEI B,et al.Tumor necrosis factor-stimulated gene-6 ameliorates early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome-mediated astrocyte pyroptosis[J].Neural Regen Res,2024,19(5):1064-1071.
[29] BAI R,LANG Y,SHAO J,et al.The role of NLRP3 inflammasome in cerebrovascular diseases pathology and possible therapeutic targets[J].ASN Neuro,2021,13:17590914211018100.
[30] ZHANG C S,HAN Q,SONG Z W,et al.Hydrogen gas post-conditioning attenuates early neuronal pyroptosis in a rat model of subarachnoid hemorrhage through the mitoK(ATP)signaling pathway[J].Exp Ther Med,2021,22(2):836.
[31] DUAN J,YUAN W,JIANG E,et al.PGAM5 promotes RIPK1-PANoptosome activity by phosphorylating and activating RIPK1 to mediate PANoptosis after subarachnoid hemorrhage in rats[J].Exp Neurol,2025,384:115072.
[32] WU Y,XU Y,SUN J,et al.Inhibiting RIPK1-driven neuroinflammation and neuronal apoptosis mitigates brain injury following experimental subarachnoid hemorrhage[J].Exp Neurol,2024,374:114705.
[33] YUAN S,YU Z,ZHANG Z,et al.RIP3 participates in early brain injury after experimental subarachnoid hemorrhage in rats by inducing necroptosis[J].Neurobiol Dis,2019,129:144-158.
[34] YANG C,LI T,XUE H,et al.Inhibition of necroptosis rescues SAH-induced synaptic impairments in hippocampus via CREB-BDNF pathway[J].Front Neurosci,2019,12:990.
[35] ADAMEOVA A,HORVATH C,ABDUL-GHANI S,et al.Interplay of oxidative stress and necrosis-like cell death in cardiac ischemia/reperfusion injury:A focus on necroptosis[J].Biomedicines,2022,10(1):127.
[36] CHEN T,PAN H,LI J,et al.Inhibiting of RIPK3 attenuates early brain injury following subarachnoid hemorrhage:Possibly through alleviating necroptosis[J].Biomed Pharmacother,2018,107:563-570.
[37] QIU X,TAO Q,ZHANG L,et al.Deletion of Bak1 alleviates microglial necroptosis and neuroinflammation after experimental subarachnoid hemorrhage[J].J Neurochem,2023,164(6):829-846.
[38] CHEN J,JIN H,XU H,et al.The neuroprotective effects of necrostatin-1 on subarachnoid hemorrhage in rats are possibly mediated by preventing blood-brain barrier disruption and RIP3-mediated necroptosis[J].Cell Transplant,2019,28(11):1358-1372.
[39] XU H,CAI Y,YU M,et al.Celastrol protects against early brain injury after subarachnoid hemorrhage in rats through alleviating blood-brain barrier disruption and blocking necroptosis[J].Aging,2021,13(12):16816-16833.
[40] YANG M F,SUN S Y,LV H G,et al.Ravoxertinib improves long-term neurologic deficits after experimental subarachnoid hemorrhage through early inhibition of Erk1/2[J].ACS Omega,2023,8(22):19692-19704.
[41] GE S,JING Z,WANG L,et al.Iron metabolism and ferroptosis in early brain injury after subarachnoid haemorrhage[J].Mol Neurobiol,2024,61(12):10736-10746.
[42] PENG Z,DING Y N,YANG Z M,et al.Neuron-targeted liposomal coenzyme Q10 attenuates neuronal ferroptosis after subarachnoid hemorrhage by activating the ferroptosis suppressor protein 1/coenzyme Q10 system[J].Acta Biomater,2024,179:325-339.
[43] YUAN B,ZHAO X D,SHEN J D,et al.Activation of SIRT1 alleviates ferroptosis in the early brain injury after subarachnoid hemorrhage[J].Oxid Med Cell Longev,2022,2022:9069825.
[44] JIAO D,XU J,LOU C,et al.Quercetin alleviates subarachnoid hemorrhage-induced early brain injury via inhibiting ferroptosis in the rat model[J].Anat Rec,2023,306(3):638-650.
[45] LIU N,LI C,YAN C,et al.BCAT1 alleviates early brain injury by inhibiting ferroptosis through PI3K/AKT/mTOR/GPX4 pathway after subarachnoid hemorrhage[J].Free Radic Biol Med,2024,222:173-186.
[46] LEI J,SONG S,CHEN Z,et al.The protective mechanism of protein kinase R to inhibit neuronal ferroptosis in cerebral injury from subarachnoid hemorrhage[J].Brain Behav,2022,12(8):e2722.
[47] FU W,CHE X,TAN J,et al.Rasd1 is involved in white matter injury through neuron-oligodendrocyte communication after subarachnoid hemorrhage[J].CNS Neurosci Ther,2024,30(3):e14452.