Distinct role of fatty acids in regulating ferroptosis

Ferroptosis is an iron-dependent programmed cell death caused by unrestricted phospholipid peroxidation, which has been implicated in pathological process of various diseases. The execution of ferroptosis is ultimately driven by the peroxidation of specific membrane lipids. Fatty acids are key membrane lipids components and increasing evidence has shown that the initiation and execution of ferroptosis can be regulated by various fatty acids. Polyunsaturated fatty acids (PUFAs), mainly arachidonic acid (AA, C20:4) and adrenic acid (AdA, C22:4), have been identified to be the key substrates of lipid peroxidation thus promoting ferroptosis induction, whereas monounsaturated and medium-chain fatty acids have an inhibitory effect on ferroptosis. Long-chain saturated fatty acids (palmitic acid) have been found to facilitate ferroptosis. It is intriguing that ω-3 PUFAs and short-chain fatty acids can exert either inhibitory or promoting effect on ferroptosis depending on the cell type and the pathological conditions. Understanding the role of different types of fatty acids in regulating ferroptosis will promote better utilization of fatty acids to manipulate ferroptosis for managing its related diseases. However, there is no literature review that provided a comprehensive analysis of the fatty acid type-dependent regulatory role in ferroptosis regulation. In this review, we summarize current understanding of the distinct regulatory role of key different types of fatty acids in the regulation of ferroptosis and discuss the mechanisms that are involved in the differential regulatory effect on ferroptosis. We also propose the issues that should be addressed for future study on ferroptosis regulation by different types of fatty acids.