Ferroptosis
Ferroptosis is an iron-dependent form of programmed cell death driven by lipid peroxidation and accumulation of reactive oxygen species, involving GPX4 inhibition and glutathione depletion, and plays critical roles in cancer, neurodegeneration, and cell death research.
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Ferroptosis
Ferroptosis definition
Ferroptosis is another form of programmed, non-apoptotic cell death originally described in 2012. Ferroptosis refers to an iron-dependent mode of cell death defined by lipid peroxidation. The term “ferroptosis” reflects its reliance on intracellular iron. Cells undergoing ferroptosis do not display classical apoptotic or necrotic features20.
Morphological characteristics
Morphologically, ferroptotic cells lack chromatin condensation, cytoplasmic swelling, and membrane rupture. Instead, they exhibit subtler characteristics, including reduced mitochondrial size and increased membrane density. These features differentiate ferroptosis from necroptosis and other cell death pathways, highlighting its distinct structural and biochemical identity.
Molecular mechanisms
Role of lipid ROS in ferroptosis
Ferroptosis arises from the iron-dependent accumulation of lipid-reactive oxygen species (ROS). Under normal conditions, lipid peroxide accumulation is controlled by glutathione (GSH), a critical substrate for glutathione peroxidase 4 (GPX4), the only enzyme capable of reducing lipid hydroperoxides within biological membranes21.
GPX4 and antioxidant regulation
When GPX4 activity is compromised, cellular antioxidant capacity declines. This leads to the accumulation of lipid ROS, ultimately triggering ferroptosis22. The disruption of this protective mechanism represents a central event in ferroptotic cell death and underscores the importance of redox homeostasis in maintaining membrane integrity (Figure 4).
Inhibition of the glutamate/cystine antiporter, xc
Ferroptosis can be induced through inhibition of the glutamate/cystine antiporter XC−. Blocking this transporter reduces cysteine import, limiting glutathione synthesis. As glutathione levels decrease, GPX4 activity is impaired, promoting lipid ROS accumulation and initiating ferroptosis. Experimentally, XC− is inhibited using the small molecule erasatin20.
Direct inhibition of GPX4
Alternatively, ferroptosis can be triggered by directly inhibiting GPX4 activity. Small molecules such as RSL3 inhibit GPX4, bypassing upstream metabolic pathways and directly compromising the cell’s ability to detoxify lipid peroxides. This results in the rapid accumulation of lipid ROS and subsequent ferroptotic cell death23.
Unanswered questions in ferroptosis
Although key molecular components of ferroptosis have been identified, important questions remain. While necroptosis triggers have been defined using small-molecule screening approaches, the physiological triggers of ferroptosis in vivo remain to be established. The mechanisms linking lipid peroxidation to irreversible cell death also remain unclear.
Figure 4. Ferroptosis activation pathway.