HIF-1α in ischemic stroke: context-dependent roles in ferroptosis and neurovascular repair

Abstract

Stroke remains a leading cause of death and long-term disability worldwide, and effective strategies to limit ischemic injury and promote post-stroke tissue repair remain urgently needed. Ferroptosis, an iron-dependent form of regulated cell death characterized by iron accumulation and lipid peroxidation, has emerged as an important mechanism contributing to neuronal and neurovascular injury after ischemic stroke. Hypoxia-inducible factor-1α (HIF-1α), a central regulator of cellular responses to hypoxia, is closely involved in both ferroptotic injury and post-stroke neurovascular repair. In this review, we summarize current evidence on the context-dependent role of HIF-1α in ferroptosis and neurovascular repair after ischemic stroke. HIF-1α regulates ferroptosis through multiple mechanisms, including modulation of iron homeostasis, antioxidant defense, lipid metabolism, and lipid peroxidation. However, its effects are not uniformly protective or detrimental and may vary according to the severity and duration of ischemia, the timing of HIF-1α activation, the metabolic state and cellular context. Beyond ferroptosis, HIF-1α contributes to post-stroke neurovascular repair by regulating angiogenesis and vascular remodeling, blood–brain barrier restoration, neurogenesis, and neuronal remodeling. These findings suggest that HIF-1α may serve as a molecular link between ischemic injury, ferroptosis, and endogenous repair responses. Rather than simply activating or inhibiting HIF-1α, therapeutic strategies that selectively modulate HIF-1α signaling according to the stage and pathological context of ischemic stroke may provide a more rational approach to limiting ferroptotic injury while promoting neurovascular repair.