Hypoxia-inducible factor 1-alpha: a dual regulator of ferroptosis in ischemic stroke and a promising therapeutic target

Ischemic stroke (IS) is an acute cerebrovascular disorder associated with high morbidity and disability rates. Its pathogenesis is complex and involves multiple forms of cell death. Ferroptosis, a novel form of non-apoptotic cell death, plays a significant role in IS progression. Hypoxia-inducible factor 1-alpha (HIF-1α) is a critical transcription factor in hypoxic responses and exhibits either neuroprotective or neurotoxic effects in IS. Recent studies have identified HIF-1α as a key regulator of ferroptosis after IS. However, whether HIF-1α exerts a dual effect in regulating ferroptosis after IS remains unclear. To address this, we reviewed studies on the regulatory role of HIF-1α in ferroptosis. The findings indicate that HIF-1α regulates ferroptosis through mechanisms involving iron metabolism, lipid peroxidation (LPO), and oxidative stress, thereby exerting both inhibitory and promotive effects. This paradoxical characteristic may be related to dynamic changes in HIF-1α expression across different time points and varying degrees of ischemic severity. We also discuss therapeutic approaches aimed at modulating HIF-1α levels to suppress ferroptosis, including prolyl hydroxylase (PHD) inhibitors, deferoxamine (DFO), dimethyloxallyl glycine (DMOG), 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), propofol, and other natural compounds. Future studies should investigate the dynamic changes of HIF-1α in regulating ferroptosis under different ischemic durations and severities of ischemia to further clarify its dual role and facilitate the development of therapeutic strategies. Nevertheless, clinical translation of these strategies is currently limited by a narrow therapeutic window, potential side effects, and insufficient clinical validation.