Ferroptosis and Its Survivors in Kidney Injury and Repair

Ferroptosis is a distinct necrotic form of regulated cell death caused by a breakdown in membrane redox homeostasis. Accumulating evidence highlights a central role for ferroptosis in both acute and chronic kidney diseases, with proximal tubule cells being the primary target. It is tightly controlled by an intricate network of metabolic pathways for iron, lipid, and redox homeostasis, all of which are highly affected by kidney diseases. Moreover, recent studies have demonstrated that several human kidney disease genes modulate cellular susceptibility to ferroptosis by altering these metabolic pathways, underscoring ferroptosis as a potential therapeutic target to improve patient outcomes. Mechanistic studies have defined the cysteine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis as the central defense against ferroptosis. GPX4 detoxifies membrane phospholipid hydroperoxides, thus preventing iron-dependent lipid peroxidation chain reactions and damage to the plasma membrane. When GPX4 is overwhelmed, toxic lipid peroxides accumulate and disrupt membrane integrity—a process known as ferroptotic stress—ultimately leading to plasma membrane rupture and cell death. In this review, we provide a conceptual framework for understanding how ferroptotic stress contributes to kidney disease progression and how it can be therapeutically targeted. We highlight recent evidence that ferroptotic stress not only triggers cell death but also significantly affects the surviving proximal tubule cells. We discuss sex-specific differences in ferroptosis and explore the implications of female resilience to ferroptosis for identifying new therapeutic strategies. By integrating mechanistic insights into ferroptotic stress with new experimental observations, this review underscores ferroptosis as both a pathogenic driver and a promising therapeutic target in kidney disease.

Duke Scholars

Author Tomokazu Souma Medicine, Nephrology