Ferroptosis in Cancer Therapy

Ferroptosis is a type of programmed cell death caused by iron overload. Unlike other forms of cell death, it occurs through lipid peroxidation, where reactive iron damages the fats in cell membranes until the cell cannot survive. This process is gaining attention in cancer therapy, particularly for tumors that resist standard treatments.

How does ferroptosis work?

Inside cells, redox-active iron participates in the Fenton reaction, converting hydrogen peroxide into highly reactive radicals. These radicals attack the lipids in cell membranes, causing chain reactions of damage. Normally, cells defend themselves using the enzyme glutathione peroxidase 4 (GPX4), which neutralizes lipid peroxides. When GPX4 is blocked or depleted, lipid damage accumulates, the cell membrane ruptures, and the cell dies. Shrunken mitochondria with dense membranes are a hallmark of ferroptosis.

Why are cancer cells vulnerable?

Cancer cells often have high iron requirements to support rapid growth, DNA synthesis, and energy production in mitochondria. Many aggressive tumors already maintain elevated iron levels and rely heavily on iron metabolism compared to normal cells. Some tumors also have weakened antioxidant systems due to mutations in oncogenes or tumor suppressors. This combination leaves cancer cells close to a ferroptotic threshold, where small disturbances can push them into irreversible death.

Overcoming drug resistance

Tumors frequently develop resistance to chemotherapy or targeted therapies by evading apoptosis or pumping out drugs. Ferroptosis uses a completely different cell death pathway, which allows it to bypass these resistance mechanisms. This makes it a promising approach for treating drug-resistant cancers.

Strategies to trigger ferroptosis

There are two main ways to trigger ferroptosis. One increases iron-driven damage by using iron-containing nanoparticles or releasing iron inside the cell to speed up lipid peroxidation. The other reduces the cell’s antioxidant defenses by blocking GPX4 or cystine uptake, making the cell less able to protect itself from oxidative stress. Both methods push cancer cells toward ferroptosis while leaving normal cells mostly unharmed.

The future of ferroptosis in cancer therapy

Ferroptosis offers a new way to attack tumors by exploiting their metabolic weaknesses and overcoming drug resistance. By turning a cancer cell’s dependence on iron into a vulnerability, this approach could become a valuable addition to current cancer treatments, especially for aggressive and hard-to-treat tumors.