AMP-activated protein kinase-driven lipid droplet dynamics govern melanoma sensitivity to polyunsaturated fatty acid and iron-induced ferroptosis
Sahar Motamedi, Nina Ravoet, Jonas Dehairs, Frank Vanderhoydonc, Abril Escamilla‐Ayala, Małgorzata Alicja Śliwińska, Shuncong Wang, Jakub Idkowiak, Stefaan J. Soenen, Patrizia Agostinis, Jean‐Christophe Marine, Johannes V. Swinnen
Abstract
Ferroptosis, a regulated form of cell death driven by lipid peroxidation, holds promise for targeting treatment-resistant cancer cells. Using a panel of melanoma cell lines, we uncover variability in the timing of ferroptosis onset upon exposure to iron and polyunsaturated fatty acids (PUFAs). This heterogeneity is linked to differences in PUFA sequestration into lipid droplets (LDs) and their subcellular distribution, particularly near lipid-metabolizing organelles such as mitochondria. In late-onset models, ferroptosis is delayed by peripheral LD retention and triggered by nutrient deprivation and AMP-activated protein kinase (AMPK) activation, which promotes LD trafficking toward mitochondria. Early responders bypass this mechanism. Our findings identify nutrient status and LD dynamics as key modulators of PUFA- and iron-induced ferroptosis, offering insights for therapeutic exploitation in cancer. Ferroptosis is an iron-dependent lipid peroxidation-mediated form of cell death that holds promise for targeting treatment-resistant cancer cells. Here, the authors show that AMPK-mediated lipid droplet dynamics modulates the response to ferroptosis inducers in melanoma.