Homo sapiens Raw sequence reads. Homo sapiens

The mechanisms underlying how cells dynamically remodel membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we reported that lysophosphatidylcholine acyltransferase 1 played a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Land cycle, consequently reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage, and inhibiting ferroptosis. Furthermore, we found that tumor cells that were initially unable to colonize the subcutis formed large tumor nodules after latency was closely associated with the upregulation of LPCAT1 expression and the emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically induced ferroptosis and suppressed tumor growth. Therefore, our results unveil a plausible role for LPCAT1 in ferroptosis evasion and may represent a new target for clinical intervention in human cancer.