Lipidomics data, AMPK-mediated lipid droplet plasticity and dispersion dictate the differential sensitivity of melanoma cells to PUFA- and iron-induced ferroptosis

Treatment-resistant cancer cells often remain sensitive to ferroptosis, a lipid peroxidation-mediated form of regulated cell death emerging as a promising interventional strategy. Here, using a panel of melanoma cell lines, we find that the ability of iron and polyunsaturated fatty acids (PUFA) to evoke ferroptosis differed substantially among the models and was time-dependent (early versus late onset of ferroptosis). This difference could largely be attributed to the sequestration of PUFA into lipid droplets (LDs) and their differential subcellular (re)distribution and association with lipid-metabolizing organelles like mitochondria. We found that starvation-dependent activation of adenosine monophosphate protein kinase (AMPK) drives the relocation of LDs toward mitochondria in the late responder group. Mitochondrial inhibitors largely rescued cells from PUFA- and iron-induced ferroptosis, corroborating the involvement of mitochondria in ferroptosis induction in these models. Collectively, our work demonstrates that nutrient availability through redispersion of LDs plays a critical regulatory role in PUFA-mediated ferroptosis induction. These findings may have important implications for the further exploitation of ferroptosis in cancer treatment.