Copper potentiates PUFA-mediated antitumor activity by activating Lipophagy

Polyunsaturated fatty acids (PUFAs) have demonstrated promising anticancer properties by inducing cancer cell death and inhibiting cancer metastasis. As dynamic organelles, lipid droplets (LDs) may protect cells from PUFA-induced lipotoxicity by sequestering excess fatty acids. However, the underlying mechanisms regulating LDs dynamics in PUFA-mediated tumor cytotoxicity remain poorly understood. In this study, we report that inhibition of LDs synthesis enhances PUFA-induced cancer cell death, suggesting that LDs formation protects against PUFA cytotoxicity. We further demonstrate that copper ions potentiate the antitumor effects of PUFAs across multiple cancer cell lines primarily by promoting apoptosis rather than cuproptosis or ferroptosis. Mechanistically, copper ions significantly reduce intracellular LDs accumulation by promoting LDs degradation via activation of ATGL-dependent lipophagy. Collectively, these findings uncover a novel mechanism whereby copper ions enhance PUFA-induced tumor cell death through promoting lipophagy, which provides valuable insights for optimizing PUFA-based cancer therapies by targeting lipid metabolism and copper homeostasis.