Cell Death Signaling of Ferroptosis

Dear Colleagues,

Ferroptosis is a unique iron-dependent form of regulated cell death. The term was coined in 2012 by the lab of Dr. Brent R. Stockwell. Synthetic lethal screening studies have identified several genes responsible for ferroptosis, including those involved in amino acid and lipid metabolism. In the presence of ferroptosis-inducing agents, the iron storage protein ferritin is degraded via ferritinophagy and releases ferrous iron, which generates reactive oxygen species (ROS) through the Fenton reaction, and subsequently induces lipid peroxidation. At the same time, ferroptosis-inducing agents inhibit the biosynthesis or utilization of the antioxidant glutathione (GSH) by inhibiting the Na⁺-independent cystine–glutamate X_c⁻ antiporter, GSH synthesis, the GSH-dependent antioxidant enzyme GSH peroxidase 4 (GPX4), or glutathione S-transferase. Thus, the accumulation of lipid peroxidation and the depletion of plasma membrane polyunsaturated fatty acids have been well known to result in the lethal event of ferroptosis. Differences in genetic makeup among cancer cells also affect the pharmacodynamic response of ferroptotic agents. High-level RAS-RAF-MEK pathway activity or p53 expression may elevate the generation of ROS through mitochondrial voltage-dependent anion channel 2/3 (VDAC2/3) or inhibit cystine uptake, respectively, and sensitize cancer cells to ferroptosis. Conversely, iron chelators (e.g., desferrioxamine mesylate and deferoxamine) and lipid peroxidation inhibitors (e.g., liproxstatin, ferrostatin, and zileuton) are known to suppress ferroptosis and block pathological cell death events in the brain, kidney, and other tissues. Although ferroptosis is a unique iron-dependent form of non-apoptotic regulated cell death, emerging evidence suggests that ferroptosis shares common pathways with different types of cell death. Recent studies reveal that the ferroptotic-agent-induced endoplasmic reticulum stress response plays a pivotal role in the crosstalk between ferroptosis and other types of cell death.

The aim of this Special Issue of Cells is to highlight recent findings that advance our knowledge about the cell death signaling of ferroptosis.

Prof. Yong Lee
Guest Editor

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• ferroptosis
• apoptosis
• autophagy
• ferritinophagy
• endoplasmic reticulum stress
• glutathione
• reactive oxygen species
• lipid peroxidation
• Fenton reaction