The biphasic interactions between ferroptosis and oxidative stress: from molecular mechanisms to disease interventions.

Abstract

Ferroptosis is an iron-dependent form of programmed cell death characterized by lipid peroxidation. Oxidative stress, a pathological state of reactive oxygen species (ROS) imbalance, exerts a complex biphasic regulatory effect on it. This review elucidates that the pro-death or anti-death outcome of oxidative stress is not random but determined by an integrated decision-making framework. This framework encompasses three core dimensions: stress parameters (e.g., ROS intensity, duration, and subcellular source), cellular context (e.g., cell type, differentiation status, and biological sex), and microenvironmental signals (e.g., hypoxia and inflammation). Mechanistically, high-intensity stress promotes ferroptosis by facilitating membrane phospholipid-specific lipid peroxidation via the Fenton reaction, disrupting iron homeostasis, and depleting glutathione to inactivate GPX4. By contrast, moderate stress activates adaptive defense programs via transcription factors such as Nrf2 and FOXO, upregulating GPX4 and HO-1 and reprogramming iron and lipid metabolism to maintain homeostasis. This review is the first to systematically incorporate the FOXO transcription factor family as a key regulatory node and emphasizes that the spatiotemporal specificity of redox signaling is essential for understanding its biphasic output. We utilize newly added summary tables to conduct a comparative analysis of the context-dependent biphasic behaviors of core nodes, disease-specific biomarkers, and defense systems across various pathologies and delineate the difference between universal conserved mechanisms and disease-specific mechanisms. This synthesis advances the discussion from phenomenon to framework, deepening the understanding of pathologies like neurodegenerative diseases, cancer, and ischemia-reperfusion injury and providing a clear conceptual blueprint and translational pathway for the formulation of spatiotemporally precise therapeutic strategies.

Key Findings

• Ferroptosis is regulated biphasically by oxidative stress depending on ROS intensity, duration, and cellular context.
• High-intensity oxidative stress promotes ferroptosis through lipid peroxidation, iron homeostasis disruption, and GPX4 inactivation.
• Moderate oxidative stress activates adaptive defense via transcription factors Nrf2 and FOXO, upregulating GPX4 and HO-1 to maintain homeostasis.
• The study highlights the importance of spatiotemporal specificity in redox signaling and incorporates FOXO as a key regulatory node alongside Nrf2.
• Context-dependent biphasic behaviors of ferroptosis-related pathways vary across diseases such as neurodegeneration, cancer, and ischemia-reperfusion injury.

Clinical Significance

Citation

He Shuang, Zhang Zhaoqiang, Li Huanet al.. The biphasic interactions between ferroptosis and oxidative stress: from molecular mechanisms to disease interventions. Molecular biology reports. 2026-Jun-06.