Ferroptosis at high altitude: Interplay between hypobaric hypoxia and iron balance alteration in cells

Ferroptosis is a regulated, non-apoptotic form of cell death, characterized by iron-dependent lipid peroxidation. It is typically driven by glutathione depletion and failure of antioxidant defenses such as glutathione peroxidase 4 (GPX4). This cell death pathway is involved in many diseases including neurodegeneration, cancer, and ischemia-reperfusion injury. Hypobaric hypoxia (HH), resulting from reduced atmospheric pressure at high altitudes (HA), leads to oxygen scarcity and triggers compensatory mechanisms, such as increased erythropoiesis, thereby elevating the physiological demand for iron to support hemoglobin synthesis. This review aims to explore the mechanistic link between HH and ferroptosis, focusing on how iron metabolism, essential for adaptation to HA, may paradoxically predispose cells to ferroptotic death via Fe²⁺-driven oxidative stress. We analysed common molecular hallmarks of both conditions, including iron dysregulation, ROS accumulation, and redox imbalance. Furthermore, we assessed organ-specific susceptibilities and discussed therapeutic strategies targeting ferroptosis to mitigate damage induced by high altitude or hypoxia. By elucidating this connection, this review aims to provide a framework for understanding how adaptive iron utilization under hypoxic condition might intersect with pathological cell death, offering insights into potential interventions for oxidative stress-related disorders in extreme HA environment.