FERROPTOSIS

• Ferroptosis is a recently discovered form of regulated cell death that is iron-dependent and driven by lipid peroxidation. 
• It differs from traditional forms of cell death like apoptosis, necrosis, and autophagy. 
• Ferroptosis plays a crucial role in various physiological and pathological conditions, including cancer, neurodegenerative disorders, and organ failure.
• Ferroptosis is a unique cell death mechanism that occurs due to the accumulation of iron and the uncontrolled oxidation of lipids (lipid peroxidation). 
• Unlike apoptosis, which is a programmed cell death pathway involving caspases, ferroptosis is primarily driven by metabolic dysfunctions related to iron homeostasis and lipid metabolism.

Key Characteristics of Ferroptosis:

• Iron Dependency – Ferroptosis requires high levels of intracellular iron.
• Lipid Peroxidation – Excessive oxidative stress leads to the breakdown of cellular lipids.
• Mitochondrial Shrinkage – Unlike apoptosis, which involves mitochondrial swelling, ferroptotic cells show mitochondrial shrinkage and loss of membrane potential.
• Glutathione Peroxidase 4 (GPX4) Inactivation – GPX4, a critical enzyme that prevents lipid oxidation, is inhibited, leading to oxidative damage.

Mechanism of Ferroptosis

• Ferroptosis occurs when there is an imbalance between iron metabolism, lipid oxidation, and antioxidant defense mechanisms.

Iron Overload & ROS Generation

• Ferroptosis is triggered when there is an accumulation of free iron (Fe²⁺) in the cell.
• The Fenton reaction leads to excessive production of reactive oxygen species (ROS).

• This highly reactive hydroxyl radical (OH•) attacks membrane lipids, initiating lipid peroxidation.

Lipid Peroxidation & Membrane Damage

• Polyunsaturated fatty acids (PUFAs) in the cell membrane undergo peroxidation, which compromises the structural integrity of the membrane.
• ACSL4 (Acyl-CoA synthetase long-chain family member 4) facilitates lipid peroxidation by incorporating more PUFAs into membranes.
• Loss of GPX4 Activity: Normally, GPX4 protects against lipid peroxidation by reducing peroxides. In ferroptosis, GPX4 inhibition leads to an uncontrolled accumulation of toxic lipid peroxides, ultimately resulting in cell death.

Antioxidant Defense Failure

• Glutathione (GSH) is a key antioxidant that protects cells from oxidative damage.
• In ferroptosis, glutathione levels decrease, leading to reduced activity of GPX4, which further promotes oxidative stress and lipid peroxidation.

Ferroptosis & Diseases

Cancer

• Some cancer cells are resistant to apoptosis but highly susceptible to ferroptosis.
• Targeting ferroptosis can be a novel anti-cancer therapy, especially for drug-resistant tumours.
• Ferroptosis Inducers: Drugs like erastin and RSL3 selectively trigger ferroptosis in cancer cells.

Neurodegenerative Diseases

• Alzheimer’s, Parkinson’s, and Huntington’s diseases are linked to iron accumulation and oxidative stress.
• Inhibiting ferroptosis could prevent neuronal cell death and slow disease progression.
• Ferrostatin-1, a ferroptosis inhibitor, has shown potential in reducing neurodegeneration.

Acute Kidney Injury (AKI)

• Ferroptosis is involved in ischemia-reperfusion injury in kidneys.
• Targeting ferroptosis with iron chelators and antioxidants can improve kidney function.

Cardiovascular Diseases

• Atherosclerosis involves oxidative stress and lipid peroxidation, key features of ferroptosis.
• Ferroptosis is implicated in heart failure and ischemic injury.

Comparison of Ferroptosis with Other Cell Death Mechanisms