AMP-activated protein kinase-driven lipid droplet dynamics govern melanoma sensitivity to polyunsaturated fatty acid and iron-induced ferroptosis

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.

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Publication Details

Journal
Nature Communications
Published
2025-12-17
DOI
https://doi.org/10.1038/s41467-025-66113-z
Citations
2
Primary Topic
Ferroptosis and cancer prognosis
Type
article
Field-Weighted Citation Impact
3.04

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article

AMP-activated protein kinase-driven lipid droplet dynamics govern melanoma sensitivity to polyunsaturated fatty acid and iron-induced ferroptosis

Jean‐Christophe Marine, Shuncong Wang, Jonas Dehairs, Johannes V. Swinnen et al.
2 citations
Nature Communications
Ferroptosis and cancer prognosis
3.04
article

AMP-activated protein kinase-driven lipid droplet dynamics govern melanoma sensitivity to polyunsaturated fatty acid and iron-induced ferroptosis

Jean‐Christophe Marine, Shuncong Wang, Jonas Dehairs, Johannes V. Swinnen, Abril Escamilla‐Ayala, Małgorzata Alicja Śliwińska, Stefaan J. Soenen, Frank Vanderhoydonc, Sahar Motamedi, Jakub Idkowiak, Patrizia Agostinis, Nina Ravoet
article en
2 citations

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.

Nature CommunicationsVol. 16(1)
University of Pardubice (CZ), VIB-KU Leuven Center for Cancer Biology (BE), VIB-KU Leuven Center for Microbiology (BE), VIB-KU Leuven Center for Brain & Disease Research (BE), KU Leuven (BE)
Fonds Wetenschappelijk Onderzoek, KU Leuven, Kom op tegen Kanker, Vlaamse regering, Fondation contre le Cancer, Stand Up To Cancer, Interreg
Openalex Percentile: Top 7%
Ferroptosis and cancer prognosis
3.04
DOIOpen Access PDFOpenAlex
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