Researchers from Washington State University (WSU) have demonstrated a fatty acid called dihomogamma-linolenic acid (DGLA) can induce ferroptosis—an iron-dependent cell death—in an animal model and human cancer cells.

Their findings have been published in the journal Developmental Cell in a paper entitled “Dietary Lipids Induce Ferroptosis in Caenorhabditis elegans and Human Cancer Cells.”

Ferroptosis is an iron-dependent type of cell death that was discovered in recent years and has become a focal point for disease research as it is closely related to many disease processes.

“If you could deliver DGLA precisely to a cancer cell, it could promote ferroptosis and lead to tumor cell death,” Jennifer Watts, an associate professor at Washington State University and corresponding author on the paper. “Also, just knowing that this fat promotes ferroptosis might also affect how we think about conditions such as kidney disease and neurodegeneration where we want to prevent this type of cell death.”

DGLA is a polyunsaturated fatty acid found in small amounts in the human body, though rarely in the human diet. Watts has been researching dietary fats including DGLA for nearly twenty years, using the nematode Caenorhabditis elegans as an animal model. C. elegans, a microscopic worm, is often used in molecular research because it is transparent and allows scientists to easily study cell-level activity. Results found in the C. elegans cells are also often transferable to human cells.

The research team discovered that feeding nematodes a diet of DGLA-laden bacteria killed all the germ cells in the worms as well as the stem cells that make the germ cells.

“Dietary lipids impact development, homeostasis, and disease, but links between specific dietary fats and cell fates are poorly understood. Ferroptosis is an iron-dependent form of nonapoptotic cell death associated with oxidized polyunsaturated phospholipids. Here, we show that dietary ingestion of the polyunsaturated fatty acid (PUFA) dihomogamma-linolenic acid (DGLA; 20:3n-6) can trigger germ-cell ferroptosis and sterility in the nematode Caenorhabditis elegans,” write the researchers.

“Many of the mechanisms we saw in the nematodes were consistent with the hallmarks of ferroptosis in mammalian systems, including the presence of redox-active iron and the inability to repair oxidized lipids, which are like molecular executioners,” stated Marcos Perez, a WSU doctoral student and first author of the paper.

To see if the results would translate to human cells, Watts and Perez collaborated with Scott Dixon of Stanford University, who has been studying ferroptosis and its potential for battling cancer.

The researchers demonstrated that DGLA could induce ferroptosis in human cancer cells. They also found an interaction with another fatty acid class, called an ether lipid, that had a protective effect against DGLA. When they took out the ether lipids, the cells died faster in the presence of DGLA.

The researchers also demonstrated that C. elegans can be a used in animal research models in the study of ferroptosis. Watts’ team recently received a $1.4 million grant from the NIH to investigate what makes the nematode germ cells so susceptible to DGLA and explore the role of mitochondria, the cell organelles involved in burning fat and regulating metabolism, in ferroptosis.

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