The key regulator of ferroptosis: HIF-1α and its complex roles and treatment strategies in related diseases.

Ferroptosis is a form of regulated cell death characterized by dysregulated iron metabolism and accumulation of lipid peroxides, which is closely associated with various pathological conditions. Hypoxia-inducible factor 1α (HIF-1α), as the principal subunit of the hypoxia-inducible transcription factor complex, controls the balance between iron homeostasis and antioxidant defense system within the hypoxic microenvironment. In oncology, PI3K/AKT signaling pathway of some tumor cells is amplified to activate HIF-1α. Then HIF-1α upregulate the SLC7A11/GPX4 axis to evade cell death. Restoration of ferroptosis signaling through pharmacological or genetic approaches, triggers iron accumulation and the production of lipid reactive oxygen species (ROS). However, this will lead to immunogenic cell death and subsequent tumor regression. In neurodegenerative disorders, excessive iron deposition in neurons occurs and coupled with compromised antioxidant defenses. As a result, ferroptosis becomes a key pathogenic mechanism in neurodegenerative disorders. In renal pathology: activation of HIF-1α suppresses GPX4 activity to mitigate lipid ROS during acute kidney injury, thereby exerting protective effects. Under conditions of chronic diabetic hypoxia, upregulation of heme oxygenase-1 (HO-1) promotes iron release, exacerbating tubular ferroptosis and accelerating fibrotic progression. Context-specific manifestations of ferroptosis are found in various systemic diseases, where its biological outcomes are determined by the dynamic equilibrium between iron homeostasis and antioxidant mechanisms. Despite compounds targeting HIF-1α have demonstrated therapeutic potential in ferroptosis-related diseases, specialized treatment strategies still depend on the underlying pathological context. Therefore, a systematic summary of the existing molecular mechanisms and discovering new mechanisms of HIF-1α regulates ferroptosis will greatly enhance our understanding of ferroptosis-related diseases, providing novel insights for precise therapeutic approaches.