Synthesis of Plasmalogen Derivatives with Unnatural Fatty Acids as Substrates for Ferroptosis Induction

Lipid peroxidation, the key step in the ferroptosis process, requires the oxidation of the double bonds of phospholipids in cellular membrane structures. Current research on ferroptosis mechanisms and new drug development has focused on naturally occurring phospholipids with internal double bonds. However, whether unnatural terminal double bonds can be involved in ferroptosis remains to be elucidated. In this study, we introduced terminal double bonds at the sn-2 position of phospholipids (Terminal Olefin Fatty Acids, TOFA) and discovered that these artificial phospholipids can kill cells alone, without ferroptosis inducers, and can be inhibited only by some ferroptosis inhibitors, such as ferrostatin-1, liproxstatin-1, alpha-tocopherol, but not deferoxamine mesylate. Our results reveal that phospholipids with terminal double bonds can participate in ferroptosis through an atypical mechanism. Moreover, further mechanistic studies could confirm that controlling the double bond position could be useful to maneuver ferroptosis and develop new drugs.