Programmed cell death is an important biological process. It removes damaged or unnecessary cells in a controlled fashion. Ferroptosis is one of these processes. It is gaining momentum as an important process in several diseases. These include cancer, neurodegenerative disorders, and kidney disease. In this blog, we will explore the fascinating world of ferroptosis. We will focus on the role of cellular iron imbalance and the role of glutathione. We will also discuss the role of ferroptosis in kidney disease.




By Majd Isreb, MD, FACP, FASN, IFMCP

Ferroptosis: The Iron-Dependent Cell Death

Ferroptosis is a unique type of programmed cell death. Here, reactive oxygen species (ROS) and lipid peroxides accumulate in the cell. This ultimately leads to iron-dependent damage to cell membranes. The latter leads to cell death.

The name “ferroptosis” comes from the Latin word “Ferrum” (iron) and the Greek word “ptosis” (falling). The name highlights the critical role of iron in this process. Unlike apoptosis or necrosis, ferroptosis involves an imbalance in cellular iron metabolism.

Ferroptosis vs. apoptosis

Ferroptosis and apoptosis are both types of programmed cell death. Yet, they have different characteristics and mechanisms.

Apoptosis is a regulated process that occurs in response to various signals. These include DNA damage or a lack of nutrients, for example. During apoptosis, the cell undergoes a series of molecular changes. These lead to the dismantling of the cell into small fragments (apoptotic bodies). These are then removed by immune cells without causing inflammation.

In contrast, in ferroptosis, there is a buildup of specific lipids. Phospholipids contain polyunsaturated fatty acids that make them vulnerable to oxidation. Excess iron in the cell reacts with hydrogen peroxide (H2O2), forming reactive oxygen species (ROS). ROS, in turn, reacts with the phospholipids of the cell membrane. This forms lipid peroxides which end up accumulating in the cell. The process ends up damaging the cell membrane in an iron-dependent manner. It leads to a loss of membrane integrity and, ultimately, cell death. Ferroptosis, unlike apoptosis, does not release apoptotic bodies but can induce inflammation.


ferroptosis at the cellular level
Courtesy httpswwwfrontiersinorgarticles103389fphar201700992full


Cellular Iron Imbalance and Ferroptosis

Cellular iron imbalance is a key trigger of ferroptosis. Iron, an essential element for various cellular processes, can be beneficial and detrimental. Excess iron can react with oxygen generating ROS. ROS, in turn, causes oxidative damage to lipids, proteins, and DNA. Ferroptosis occurs when there is a disruption in cellular iron metabolism. This disruption leads to iron accumulation and then lipid peroxidation.

Studies have shown that iron chelators block ferroptotic cell death. In addition, various iron transporters are involved in iron metabolism. Mutations in iron transporter genes and external stressors can contribute to iron imbalance.


Clearly filtered


The Role of Glutathione in Ferroptosis

Glutathione is a tripeptide molecule composed of glutamate, cysteine, and glycine. It is a potent cellular antioxidant that scavenges and neutralizes ROS. This makes it a master antioxidant because it protects cells from oxidative stress. In ferroptosis, there is a disruption in the balance between glutathione and ROS. Depletion of glutathione leads to an accumulation of lipid peroxides. These, in turn, disrupt cell membrane integrity and promote ferroptosis, as we saw.

Several factors can cause the depletion of glutathione in the cells. The enzyme glutathione peroxidase 4 (GPX4) is a regulator of ferroptosis. It depends on the availability of glutathione to function. Lower glutathione levels decrease the activity of GPX4. This, again, causes the accumulation of lipid peroxide and ferroptosis.

Similarly, cystine is an oxidized form of the amino acid cysteine. It is a precursor for glutathione synthesis and can regulate ferroptosis. There is a specific system that transports cystine into cells. This cystine/glutamate antiporter system Xc- plays critical for maintaining intracellular glutathione levels. Inhibition of this system can lead to cystine depletion. This, in turn, causes glutathione depletion and ferroptosis.

Inhibition of Cystine/Glutamate Antiporter System

The cystine/glutamate antiporter system Xc- regulates intracellular glutathione levels. Various factors can inhibit this antiporter. Compounds like erastin and sulfasalazine can inhibit it. These compounds can cause glutathione depletion and trigger ferroptosis. Oxidative stress, amino acid imbalances, and certain chemotherapeutic drugs can also disrupt it.

Kidney Disease Implications

Ferroptosis plays a role in various kidney diseases. These include acute kidney injury (AKI), chronic kidney disease (CKD), and kidney cancer. In AKI, factors such as ischemia-reperfusion injury and drug nephrotoxicity can trigger ferroptosis. This causes renal cell death and kidney damage.

Iron metabolism is dysregulated in CKD. Glutathione balance is also disturbed. Both of these factors contribute to the progression of CKD. There is an increasing body of evidence indicating that ferroptosis is involved in the progression of CKD.

This highlights the crucial role of oxidative stress in kidney injury and disease. It also emphasizes the need to support glutathione in kidney patients. Iron metabolism and regulation may be another target to slow the progression of CKD.

Join us to end the kidney disease epidemic and receive the FREE Report “5 Pitfalls to Avoid When Caring for Kidney Patients”

The bottom line

Ferroptosis is an iron-dependent form of programmed cell death. It has emerged as a significant player in kidney diseases. Disturbances in cellular iron metabolism and glutathione levels contribute to oxidative stress. This causes lipid peroxidation of cell membranes and then death in renal cells. Ferroptosis is a link between iron metabolism, oxidative stress, glutathione, and kidney injury. It plays an important role in the progression of kidney disease.