Non‐Mammalian Models in Ischemic Stroke Research: Advances, Applications, and Translational Potential

Ischemic stroke remains a major global health burden, consistently ranking among the leading causes of mortality and long-term disability. Although rodent models are widely utilized for ischemic stroke research, their limited translational success has driven the pursuit of alternative experimental systems. This review underscores the growing significance of non-mammalian models, particularly zebrafish and Drosophila melanogaster, in advancing ischemic stroke research. Zebrafish offer notable advantages, including high genetic homology with humans, optical transparency, a pronounced capacity for neural regeneration, in vivo live real-time imaging, and behavioral analyses. Photothrombotic and systemic hypoxia paradigms in zebrafish enable detailed investigation of neurovascular injury and recovery processes. Drosophila, characterized by a rapid life cycle and sophisticated genetic toolkit, serves as a valuable model for elucidating hypoxia-induced neuronal damage and stroke-related comorbidities such as sleep disturbances. These models are cost-efficient, ethically advantageous, and well-suited for high-throughput applications. Despite inherent anatomical and physiological disparities, non-mammalian systems provide critical complementary insights into stroke pathogenesis and therapeutic innovation, reinforcing their integration into multi-model research frameworks.