Regulatory mechanisms of hypoxia-inducible factors on ferroptosis in ischemic stroke

Ischemic stroke remains a primary contributor to global disability and mortality, primarily resulting from interruptions in cerebral blood flow that trigger brain tissue necrosis. Among the various mechanisms of cell death, ferroptosis assumes a key role in the pathophysiology of cerebral infarction. Hypoxia-inducible factors (HIFs) are central to cellular adaptation under hypoxic conditions and exhibits dual regulatory roles in neuronal ferroptosis. This review delineates the intricate mechanisms by which HIF-1α and the less-characterized HIF-3α modulate ferroptosis in ischemic stroke. We detail how HIF-1α promotes ferroptosis by disrupting iron homeostasis, amplifying lipid peroxidation, and activating inflammatory networks, while also highlighting its context-dependent protective functions. Furthermore, we explore the emerging role of HIF-3α, particularly its mitochondrial localization and diverse functions conferred by alternative splicing variants, which may oppose HIF-1α-driven ferroptosis. By synthesizing the distinct regulatory networks of HIF-1α and HIF-3α, this review underscores their potential as therapeutic targets and proposes that selective modulation of these pathways could offer novel neuroprotective strategies for ischemic stroke.