Sphk2 in ischemic stroke pathogenesis: Roles, mechanisms, and regulation strategies

IF 12.4 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews Pub Date : 2025-07-25 DOI:10.1016/j.arr.2025.102844

Mengzhao Feng , Qi Qin , Kaiyuan Zhang , Fang Wang , Dengpan Song , Mengyuan Li , Yuan An , Zhihua Li , Fuyou Guo

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引用次数: 0

Abstract

Ischemic stroke, a leading cause of mortality and long-term disability worldwide, is characterized by acute cerebral artery occlusion leading to neuronal death and functional deficits. Despite advances in reperfusion therapies, the lack of effective neuroprotective agents underscores the need for novel therapeutic strategies targeting secondary injury mechanisms. Sphingosine kinase 2 (Sphk2) has emerged as a pivotal regulator in ischemic stroke pathogenesis, mitigating blood-brain barrier leakage, neuroinflammation, and neuronal survival through its downstream metabolite, sphingosine-1-phosphate. This review comprehensively examines the roles and mechanisms of Sphk2 in ischemic stroke, highlighting its potential in anti-inflammation and neuroprotection. We discuss current therapeutic approaches targeting Sphk2, including pharmacological activation, natural compounds and gene therapy. Future directions focus on developing Sphk2-specific agonists, optimizing delivery strategies, and exploring cell type-specific adeno-associated virus vectors and engineered exosomes modulation to maximize therapeutic efficacy while minimizing off-target effects. By synthesizing current knowledge and identifying gaps, this review provides a roadmap for harnessing Sphk2 as a therapeutic target to improve stroke outcomes.

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Sphk2在缺血性卒中发病机制中的作用、机制和调控策略

缺血性中风是世界范围内死亡和长期残疾的主要原因，其特点是急性脑动脉闭塞导致神经元死亡和功能缺陷。尽管再灌注治疗取得了进展，但缺乏有效的神经保护剂强调了针对继发性损伤机制的新治疗策略的必要性。鞘氨醇激酶2 （Sphk2）已成为缺血性卒中发病机制的关键调节因子，通过其下游代谢物鞘氨醇-1-磷酸减轻血脑屏障渗漏、神经炎症和神经元存活。本文综述了Sphk2在缺血性卒中中的作用和机制，强调了其在抗炎症和神经保护方面的潜力。我们讨论了目前针对Sphk2的治疗方法，包括药物激活、天然化合物和基因治疗。未来的研究方向是开发sphk2特异性激动剂，优化递送策略，探索细胞类型特异性腺相关病毒载体和工程外泌体调节，以最大限度地提高治疗效果，同时最大限度地减少脱靶效应。通过综合目前的知识和识别差距，本综述为利用Sphk2作为治疗靶点来改善卒中预后提供了路线图。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Ageing Research Reviews 医学-老年医学

CiteScore

19.80

自引率

2.30%

发文量

216

审稿时长

55 days

期刊介绍： With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.