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Proteasome-dependent degradation of DAPK1 by wogonoside blocks PARthanatos and protects against ischemic stroke 期刊论文

编号：

22DD3CF6F637E17F1BF7D5425FD7A33B
作者：

Zhai, ChunZe#^[1,2]Cao, Yin^[1,2];Shen, YuXin^[1,2];Wang, YiZhe^[1,2];Liu, ZhiPeng^[1,2];Liu, Fang^[1,2];Yu, JinLiu^[1,2];Wang, XiuXiu^[2];Zhang, ZhaoHuan(张照环)*^[1,3]Xu, XiaoHui(徐晓辉)*^[1,2]
语种：

英文
期刊：

NEUROPHARMACOLOGY ISSN：0028-3908 2026 年 301 卷 ; DEC 15
收录：
关键词：

PARthanatos DAPK1 Wogonoside Proteasomal degradation Ischemic stroke
摘要：

Ischemic stroke remains a leading cause of death and disability, yet effective pharmacological neuroprotection remains elusive. ROS-induced PARthanatos-driven by PARP1 hyperactivation and the mitochondrial-apoptosis-inducing factor (AIF) death axis-is a principal executor of ischemic neuronal death. However, direct PARP1 inhibition inevitably compromises essential DNA repair. Here, we identify a downstream intervention node that uncouples lethal signaling from genomic maintenance. Through phenotype-to-target deconvolution combining reverse pharmacophore mapping, bioinformatic intersection with programmed cell death genes, and integrated biophysical validation (docking, 100-ns molecular dynamics, cellular thermal shift assay, and surface plasmon resonance), we demonstrate that wogonoside (WS), a flavonoid glycoside from Scutellaria baicalensis, directly binds death-associated protein kinase 1 (DAPK1; KD = 6.07 mu M) and acts as a ligand-induced degrader that triggers proteasome-dependent DAPK1 clearance. CRISPR/Cas9-mediated DAPK1 knockout fully phenocopied WS-mediated protection, whereas ectopic DAPK1 overexpression abolished it. WS-induced degradation intercepted the JNK-mitochondrial depolarization-AIF nuclear translocation cascade while leaving PARP1 catalytic activity, PAR polymer formation, and gamma H2AX resolution fully intact-in stark contrast to the clinical PARP1 inhibitor olaparib. In a mouse permanent distal middle cerebral artery occlusion model, a single dose of WS reduced cortical infarct volume by similar to 50%, preserved neurons, suppressed microglial activation, and maintained microvascular integrity, accompanied by significant sensorimotor recovery. Single-nucleus RNA sequencing revealed Dapk1 enrichment in activated microglia and co-variation with neuronal MAPK pro-death signaling, suggesting a dual-compartment mechanism. These findings define proteasome-dependent DAPK1 degradation as a mechanistically distinct antioxidant strategy for acute ischemic stroke.
推荐引用方式
GB/T 7714：

Zhai Chun-Ze,Cao Yin,Shen Yu-Xin, et al. Proteasome-dependent degradation of DAPK1 by wogonoside blocks PARthanatos and protects against ischemic stroke [J].NEUROPHARMACOLOGY,2026,301.
APA：

Zhai Chun-Ze,Cao Yin,Shen Yu-Xin,Wang Yi-Zhe,&Xu Xiao-Hui.(2026).Proteasome-dependent degradation of DAPK1 by wogonoside blocks PARthanatos and protects against ischemic stroke .NEUROPHARMACOLOGY,301.
MLA：

Zhai Chun-Ze, et al. "Proteasome-dependent degradation of DAPK1 by wogonoside blocks PARthanatos and protects against ischemic stroke" .NEUROPHARMACOLOGY 301(2026).
入库时间：

10/18/2026 9:56:32 PM
更新时间：

10/18/2026 9:56:32 PM

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