2. Academic Validation
  3. Targeting RIPK1-mediated necroptosis, oxidative stress, and ferroptosis: A novel multitarget therapy for ischemic stroke

Targeting RIPK1-mediated necroptosis, oxidative stress, and ferroptosis: A novel multitarget therapy for ischemic stroke

  • Eur J Med Chem. 2025 Oct 15:296:117884. doi: 10.1016/j.ejmech.2025.117884.
Ziwei Song 1,  Liang Ye 2,  Yunjie Wang 1,  Wenyan Wang 1,  Chunjiao Liu 3,  Jing Lu 1,  Jiajing Zhang 4,  Hongbo Wang 5,  Jianzhao Zhang 6,  Yifei Yang 7,  Jingwei Tian 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China.
  • 2 School of Public Health, Binzhou Medical University, Yantai, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China.
  • 3 State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China.
  • 4 State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China; School of Pharmacy, Binzhou Medical University, Yantai, 264003, China.
  • 5 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China.
  • 6 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China. Electronic address: zhangjianzhao@163.com.
  • 7 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China. Electronic address: yangyifei@luye.com.
  • 8 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China. Electronic address: Tianjingwei618@163.com.
PMID: 40582188 DOI: 10.1016/j.ejmech.2025.117884
Abstract

Ischemic stroke is characterized by high mortality and disability rates, and involves complex pathological processes mediated by multiple damage cascade mechanisms. While current clinical investigational drugs predominantly target antioxidant stress pathways, there remains an urgent need for multi-target therapeutic agents with enhanced therapeutic potential. Notably, RIPK1-mediated Necroptosis and neuroinflammation have emerged as critical drivers of secondary brain injury, impacting stroke severity and clinical prognosis. Guided by these mechanistic insights, we rationally designed and synthesized a structurally diverse series of novel 4,5-dihydro-1H-pyrazole derivatives, followed by comprehensive biological evaluations. Compound 23a demonstrated potent RIPK1 kinase inhibitory activity (IC50 = 0.115 μM), and exhibited superior antioxidant efficacy (IC50 = 9.72 μM) compared to the clinically approved drug edaravone (IC50 = 22.79 μM). Furthermore, 23a demonstrated remarkable anti-ferroptosis activity by suppressing PTGS2 mRNA expression (IC50 = 0.156 μM). In vivo studies showed that 23a markedly reduced cerebral infarction volume and improved neurological function scores in transient middle cerebral artery occlusion (tMCAO) model, outperforming edaravone, and demonstrated multi-target effects against oxidative stress, Necroptosis, and Ferroptosis in the ischemic penumbra tissue. These findings collectively highlight 23a as a promising triple-target lead compound for ischemic stroke therapy, warranting further optimization and development.

Keywords

Ferroptosis; Ischemic stroke; Multitarget neuroprotective agents; Necroptosis; Receptor-interacting protein kinase 1.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z