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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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  • Sahar Motamedi,
  • Nina Ravoet,
  • Jonas Dehairs,
  • Frank Vanderhoydonc,
  • Abril Escamilla-Ayala,
  • Malgorzata A. Sliwinska,
  • Shuncong Wang,
  • Jakub Idkowiak,
  • Stefaan Soenen,
  • Patrizia Agostinis,
  • Jean-Christophe Marine,
  • Johannes V. Swinnen

摘要

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.