EPFL scientists have identified a molecular pathway that protects cells from lipid oxidation and ferroptosis, a regulated form of cell death involved in aging and several diseases.
Our cells constantly face oxidative stress, a natural byproduct of metabolism that can damage DNA, proteins, and lipids. Every cell must strike a delicate balance between using oxygen for life-sustaining reactions and avoiding the damage it can cause.
Lipid oxidation: useful and dangerous
Lipids are the fat molecules that form the cell's membrane among other essential structures. When they interact with oxygen molecules, they can undergo so-called "oxidative damage", which can produce toxic radicals that threaten the cell's integrity itself.
Oxidative damage to lipids is actually part of normal metabolism, but excessive oxidation, which can occur quite rapidly due to self-propagation, destabilizes membranes and triggers ferroptosis, a form of programmed cell death that is linked to aging, cancer, cardiovascular disease, neurodegeneration, and chronic inflammation.
Until now, how cells detect such lipid oxidation and mount a response remained poorly understood. Researchers have suspected that an early warning system must exist, which spots lipid stress and activates protective genes before damage becomes fatal.
The LORD pathway
Laurence Abrami and Francisco Mesquita in the group of Professor Gisou van der Goot at EPFL, has now identified that warning system as the Lipid Oxygen Radical Defense or LORD pathway. The study, in collaboration with the group of Professor Didier Trono at EPFL, shows that the LORD pathway monitors the oxidation state of cellular lipids and activates a genetic program to prevent ferroptosis by changing the cell's sensitivity to lipid peroxidation stress.
The discovery reveals a key layer of metabolic and epigenetic regulation that helps cells maintain their structural integrity under oxidative stress.
"I think it might be the biggest discovery my lab has ever made," says Gisou van der Goot. "It is a pathway by which cells can sense the oxidation of lipids and respond to it to prevent death by a pathway identified about ten years ago termed ferroptosis. This pathway is epigenetically repressed in cells and derepressed upon oxidative stress. It might be the genetic regulation of lipid quality control that the field has assumed the existence of."
Identifying the signaling pathway
The team combined data mining with epigenomic and gene‑expression profiling and functional tests to look for the cell's early warning signs that lipids are beginning to oxidize. They also checked which genes switch on or off and where key regulators sit on DNA.
The approach identified several key players in the LORD pathway: the transcription factor ZNF354A, the co-repressor KAP1, the transcriptional activator ATF2, and the histone methyltransferase SETDB1. Under normal conditions, these proteins work together to silence stress-response genes through a repressive chromatin structure. But when lipid peroxidation occurs, stress signals trigger phosphorylation of ATF2, KAP1, and ZNF354A, which disassembles the complex and lifts repression on protective genes. This in turn switches on genes involved in lipid repair and antioxidant defense.
The researchers found that lowering ZNF354A makes cells more resistant while overexpressing it makes them more sensitive to lipid oxidation and prone to ferroptosis. They also uncovered how epigenetic control helps keep defense genes off in calm conditions and allows activation during lipid stress.
Scientific and medical Implications
The discovery highlights how metabolism and epigenetics work together to maintain cellular homeostasis under stress.
In terms of medicine, the findings deepen our understanding of how cells preserve membrane integrity, a fundamental aspect of life. Because ferroptosis contributes to diseases ranging from neurodegeneration to cancer, the LORD pathway could become a promising target for therapeutic strategies. Drugs that boost this defense might protect tissues from oxidative damage, while inhibitors could sensitize cancer cells to ferroptosis-inducing treatments.
Other contributors
- Nexco Analytics
- Nanyang Technological University
