This study investigates how lipid unsaturation influences the activity of BAX and BAK, two key proteins involved in mitochondrial outer membrane permeabilization (MOMP) during apoptosis. Using lipid nanodiscs, the researchers found that apoptotic conditions lead to an enrichment of unsaturated lipids near BAK and BAX. These unsaturated lipids enhance the pore-forming activity of BAX and BAK in model membranes, isolated mitochondria, and cells. Molecular dynamics simulations further support this finding, showing that unsaturated lipids promote pore formation. The fatty acid desaturase FADS2, which is involved in lipid unsaturation, enhances apoptosis sensitivity and activates the cGAS/STING pathway downstream of mtDNA release. The levels of FADS2 correlate with the sensitivity of lung and kidney cancer cells to apoptosis when treated with unsaturated fatty acids. These findings suggest that the lipid environment around BAX and BAK plays a crucial role in regulating MOMP and apoptosis. The study highlights the importance of lipid composition in the function of BAX and BAK during apoptosis and provides insights into how lipid unsaturation may influence cancer therapy.This study investigates how lipid unsaturation influences the activity of BAX and BAK, two key proteins involved in mitochondrial outer membrane permeabilization (MOMP) during apoptosis. Using lipid nanodiscs, the researchers found that apoptotic conditions lead to an enrichment of unsaturated lipids near BAK and BAX. These unsaturated lipids enhance the pore-forming activity of BAX and BAK in model membranes, isolated mitochondria, and cells. Molecular dynamics simulations further support this finding, showing that unsaturated lipids promote pore formation. The fatty acid desaturase FADS2, which is involved in lipid unsaturation, enhances apoptosis sensitivity and activates the cGAS/STING pathway downstream of mtDNA release. The levels of FADS2 correlate with the sensitivity of lung and kidney cancer cells to apoptosis when treated with unsaturated fatty acids. These findings suggest that the lipid environment around BAX and BAK plays a crucial role in regulating MOMP and apoptosis. The study highlights the importance of lipid composition in the function of BAX and BAK during apoptosis and provides insights into how lipid unsaturation may influence cancer therapy.