A team at McGill University studying ferroptosis, a form of cell death, have discovered that the process begins deep inside the cell, a finding that could lead to new treatments for cancer and neurodegenerative diseases.

Using antioxidant probes that light up as they are consumed, the team tracked ferroptosis in real time and identified the endoplasmic reticulum (ER) as the key cellular structure where the process first takes hold. Protecting the ER and the lysosome, they found, can halt ferroptosis entirely.

“Ferroptosis has therapeutic potential in cancer treatment and neurodegenerative diseases,” said Gonzalo Cosa, professor in McGill’s Department of Chemistry and senior author on the study. “But until now, we didn’t know how it starts or propagates. This information is critical toward understanding the action of current ferroptosis inducers and inhibitors.”

“Our results show that protecting the ER and lysosomes can abort ferroptosis,” said Cosa. “In contrast, protecting the outer leaflet of the plasma membranes does not impact ferroptosis evolution.”

Implications for cancer, neurodegenerative disorders

Ferroptosis kills cells by triggering runaway chemical reactions that damage fats in cell membranes. In cancer, deliberately triggering ferroptosis could stop tumour growth. In Alzheimer’s, Parkinson’s and other conditions, slowing down ferroptosis could protect healthy brain cells.

“Understanding the molecular action of new forms of cell death is critical in health,” said Cosa. “Such an understanding paves the way for the development of better therapies.”

A new window into cell death

The researchers’ custom-built fluorogenic antioxidants acted as beacons, revealing when and where in the cell, lipid damage began. The research work offers a powerful new platform to study drugs designed to either block or induce ferroptosis.

“These antioxidants further enable enhanced resolution and visualization of the evolution of this form of cell death, providing unprecedented molecular information at the cellular level,” said Cosa.