Ferroptosis is a form of regulated cell death discovered in 2012 that depends on iron and is characterized by the accumulation of lipid-based reactive oxygen species (ROS). It is biochemically and morphologically different from other known forms of cell death. This mechanism plays a role in a wide range of physiological and pathological conditions, from cancer to neurodegeneration, highlighting its importance in human health.
The Molecular Chain Reaction of Ferroptosis
The initiation of ferroptosis is linked to an excess of available iron within a cell. This iron, in its ferrous (Fe2+) state, acts as a catalyst in a destructive process. It participates in reactions that generate highly reactive molecules, which in turn attack components of the cell membrane. This catalytic activity of iron is a requirement for this pathway of cellular demise.
This process specifically targets polyunsaturated fatty acids (PUFAs), which are abundant in cellular membranes. These lipids are the primary substrate for an oxidative process called lipid peroxidation. Similar to metal rusting, the PUFAs are “oxidized,” leading to a chain reaction that produces lipid peroxides.
This destructive chain reaction takes hold when a cell’s primary protective mechanism against lipid peroxidation fails. The enzyme glutathione peroxidase 4 (GPX4) neutralizes lipid peroxides by converting them into non-toxic alcohols. Ferroptosis is triggered when GPX4 is inhibited or when its cofactor, glutathione, is depleted. Without a functional GPX4 defense system, lipid peroxidation runs unchecked, causing membrane damage that leads to cell rupture.
How Ferroptosis Differs From Other Cell Death
Cell death can occur through various organized or chaotic processes. One well-studied form is apoptosis, a highly regulated and orderly process where the cell breaks itself down. It shrinks and packages its contents into small bodies, allowing neighboring cells to clean up the debris without an inflammatory response.
Another form of cell death is necrosis, which results from acute injury, such as from trauma or a lack of blood supply. The cell swells, its outer membrane bursts, and its internal contents spill into the surrounding tissue. This process causes significant local inflammation as the immune system responds to the damage.
Ferroptosis stands apart from both apoptosis and necrosis. Unlike the orderly dismantling of apoptosis or the chaotic bursting of necrosis, its defining features are a dependence on iron and lipid peroxidation. Morphologically, cells undergoing ferroptosis exhibit unique changes, such as shrunken mitochondria with increased membrane density. It also does not involve the caspase enzymes that drive apoptosis or the regulators associated with necrosis.
The Connection Between Ferroptosis and Disease
Ferroptosis plays a dual role in human health, acting as both a contributor to disease and a potential therapeutic tool. In neurodegenerative diseases like Parkinson’s and Alzheimer’s, ferroptosis contributes to the loss of neurons. Increased iron levels and lipid peroxidation products have been observed in the brains of patients with these conditions. In cases of stroke or heart attack, the reperfusion of blood to oxygen-starved tissues can trigger ferroptosis, causing further damage in an ischemia-reperfusion injury. Researchers are exploring strategies to inhibit ferroptosis to protect healthy cells.
Conversely, harnessing ferroptosis is a promising strategy in the fight against cancer. Many tumor cells develop resistance to traditional forms of programmed cell death like apoptosis, which allows them to survive. These resistant cancer cells have a high metabolism that makes them particularly vulnerable to ferroptosis. Their increased iron uptake and lipid synthesis create a biochemical environment for this type of cell death. Scientists are developing drugs that can induce ferroptosis, offering a method to eliminate cancer cells that evade other treatments.