Lipid droplets accumulate and delay regulated cell death execution

Summary Normal and cancer cells accumulate lipid droplets (LDs) under stress to buffer lipotoxicity, but their role in regulated cell death (RCD) remains incompletely understood. Here, we explored LD accumulation across diverse apoptotic and non-apoptotic RCD modalities in human cancer cells and Drosophila germ cells. We found that LD accumulation arises from de novo LD biogenesis, whereas LD lipolysis remains active—or even enhanced—in dying germ cells and cancer cells, respectively. In Drosophila, LD accumulation in the Brummer lipase mutant inhibited germ cell death, indicating a protective function. Proteomic and imaging analyses revealed a broad redistribution of LD-associated proteins, encompassing lipid metabolism and stress response factors, as well as the pro-apoptotic effector Bax in human cancer cells. Enhanced LD–mitochondria contacts promoted active Bax translocation from mitochondria to LDs, thereby delaying apoptosis execution. Conversely, depletion of LDs sensitized cells to Bax- or truncated Bid-induced apoptosis. Collectively, these findings define LD accumulation during cell death as a delaying mechanism in which LDs sequester mitochondrial cell death regulators, attenuating their pro-death activity and revealing potential therapeutic implications for apoptosis-resistant cancers.