PUFAs dictate the balance of power in ferroptosis.

• The flippase SLC47A1 is a repressor of ferroptosis. • PPARA transactivates SLC47A1 to suppress ferroptosis induction through lipid remodeling. • Knockdown of SLC47A1 sensitizes cells to ferroptosis in a ACSL4-SOAT1–axis dependent manner to generate polyunsaturated fatty acid containing (PUFA) cholesterol esters. • Net effect of acyl-PUFAs with various head groups promotes ferroptosis. Ferroptosis is an iron-dependent form of cell death triggered by dysregulation of biochemical processes that culminate in lethal lipid peroxidation. Lipid metabolism is fundamental for determining ferroptotic fate, however, the mechanisms that alter lipid components to shape ferroptosis susceptibility remains elusive. A recent article by Lin and colleagues in Nature Communications systematically analyzed phospholipid transporters (phospholipid scramblases, flippases, and floppases), and identified that the lipid flippase solute carrier family 47 member 1 (SLC47A1) functions as a regulator of lipid remodeling and promotes ferroptosis resistance. SLC47A1 is transactivated by peroxisome proliferator activated receptor alpha (PPARA). Upon ferroptosis induction, SLC47A1 upregulation inhibits DHA/DPA polyunsaturated fatty acid containing glycerophospholipids (PUFA-PLs) accumulation to block ferroptosis. Depletion of either PPARA or SLC47A1 sensitized cells to ferroptosis by favoring ACSL4-SOAT1–mediated production of polyunsaturated fatty acid containing (PUFA) cholesterol esters. Ferroptosis has been widely linked to degenerative processes and tumor suppression. These findings indicate that lipid transporters may provide yet another means by which PUFA-containing membrane lipids convey ferroptosis sensitivity. [ABSTRACT FROM AUTHOR]