Can Iron and Polyunsaturated Fatty Acid Supplementation Induce Ferroptosis?

Abstract

Ferroptosis is a regulated non-apoptotic cell death process triggered by excessive iron-induced lipid peroxidation. Excess intracellular iron promotes lipid peroxidation by increasing reactive oxygen species formation through the Fenton reaction. Thus, iron and polyunsaturated fatty acid intake may trigger ferroptosis under certain conditions. The aims of this review were to compile and examine evidence in the literature for the effects of iron and polyunsaturated fatty acid supplementation on ferroptosis. Omega-6 polyunsaturated fatty acids have relatively greater susceptibility to lipid peroxidation and could, therefore, participate in ferroptosis. By contrast, omega-3 polyunsaturated fatty acids promote intracellular antioxidants synthesis and reduce the formation of hydroperoxides that induce ferroptosis. As intestinal iron absorption is regulated by iron nutritional status, individuals with normal functioning of the hepcidin-ferroportin axis are at low risk of developing iron overload in response to ingestion of iron-rich foods. Therefore, iron supplementation is potentially toxic mainly for the intestinal epithelium and the microbiota. In animal models, iron-rich diets increased oxidative damage, lowered the glutathione concentration within hepatocytes, and downregulated desaturases that synthesize long-chain polyunsaturated fatty acids. These adverse effects of iron supplementation were prevented by omega-3 fatty acid co-supplementation. The impact of food and supplement intake on ferroptosis has seldom been investigated. Scientific evidence still does not allow us to know for sure whether iron and PUFA supplementation are capable of inducing ferroptosis. As the mechanisms that control ferroptosis can determine whether cells proliferate or die, future studies should directly investigate the effects of nutrient supplementation and food intake on the ferroptosis process in different types of cells and tissues.

Effects of eicosapentaneoic acid on innate immune responses in an Atlantic salmon kidney cell line in vitro

“…The enrichment of upregulated transcripts in the ferroptosis pathway may indicate that these high levels of cellular EPA in combination with a strong interferon inducer like poly I:C, induce generation of lipid peroxide formation [ 93 ]. The combination of these factors with the observation that ASK cells express high levels of ferritin mRNA (suggestive of high iron load) may lead to ferroptosis [ 94 ]. Ferroptosis can be described as a regulated nonapoptotic cell death caused by iron-dependent accumulation of reactive oxygen species (ROS) [ 95 ].…”

Lipid Peroxidation of the Docosahexaenoic Acid/Arachidonic Acid Ratio Relating to the Social Behaviors of Individuals with Autism Spectrum Disorder: The Relationship with Ferroptosis

“…Therefore, the imbalance between the DHA levels and ARA levels in plasma may induce ferroptosis and contribute to the pathophysiology of ASD. Importantly, such imbalances between omega-3 and omega-6 PUFAs are determinative in neurocognitive disorders [62], and an increase in omega-6 PUFAs induce peroxidation and ferroptosis [63]. Therefore, an unbeneficial DHA/ARA ratio of 0.57 due to higher plasma ARA levels may reflect an imbalance between omega-3 and omega-6 PUFAs in plasma may induce ferroptosis, resulting in important mechanisms causing neurocognitive disorders, such as ASD.…”

Hacking the Lipidome: New Ferroptosis Strategies in Cancer Therapy

“…PUFA-PLs are the main participant in peroxidation in ferroptosis; however, omega-3 PUFAs support transcription factors which enhance antioxidant systems and reduce lipid peroxidation via ferroptosis [ 110 ]. Therefore, they have potential as ferroptosis inhibitors.…”

“…Supplementation of polyunsaturated fatty acids (PUFAs) prior to ferroptosis-inducing treatment has been shown to sensitize cells. Omega-6 PUFAs are more prone to peroxidation than omega-3 PUFAs, making them more likely to contribute to ferroptosis and enhance its effects [ 110 ].…”