Phospholipids with two polyunsaturated fatty acyl tails: an important driver of ferroptosis

We highlight the latest work of Qiu et al. on the core mechanism of ferroptosis induced by rare phospholipids with two polyunsaturated fatty acyl tails (PL-PUFA₂s), which has been published in Cell. It has long been acknowledged that PLs containing one PUFA tail (PL-PUFA₁s) serve as substrates for phospholipid peroxidation during the process of ferroptosis, owing to their susceptibility to oxidation and prevalence in vivo. However, the authors note that PL-PUFA₂s, rather than PL-PUFA₁s, represent critical lipid classes involved in the pro-ferroptosis process. Exogenous phosphatidylcholine-PUFA₂s accumulate in mitochondria and combine with Complex I within the electron transport chain, thereby potentially resulting in an elevation of mitochondrial reactive oxygen species levels. Then, these mitochondrial peroxides prompt the substantial accumulation of peroxides within the endoplasmic reticulum, ultimately culminating in ferroptosis. These findings shed light on the potential molecular mechanisms underlying the induction of ferroptosis by dietary PL-PUFA₂s and offer novel insights for both the evaluation of cellular iron death sensitivity and the treatment of cancer. This article will provide a more comprehensive elucidation of the paper and facilitate an enhanced understanding of the underlying mechanisms for readers.