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<p>Ferroptosis—an iron-dependent form of cell death triggered by phospholipid peroxidation—has emerged as a promising therapeutic avenue in cancer treatment. Although neuroblastoma (NB) has been identified as a ferroptosis susceptible cancer, our studies reveal striking heterogeneity in ferroptosis sensitivity across high-risk NB models. Through a targeted metabolic compound screen, we identified stearoyl-CoA desaturase 1 (SCD1)—a key enzyme in monounsaturated fatty acid (MUFA) synthesis—as a robust ferroptosis-sensitizing target. Genetic and pharmacological inhibition of SCD1 restored ferroptosis sensitivity in resistant NB cells. Notably, high SCD1 expression correlates with poor patient prognosis. Co-treatment with arachidonic acid (AA), a polyunsaturated fatty acid (PUFA), further enhanced ferroptotic cell death via increased PUFA/MUFA ratio. Nevertheless, neither baseline lipidomic profiles nor transcriptomes of key ferroptosis regulators reliably predicted ferroptosis sensitivity. To overcome AA’s poor solubility, we engineered AA-loaded lipid nanoparticles (AA-LNPs), which selectively accumulated in high-risk NB tumors and synergized with SCD1 inhibition. This dual-sensitization strategy, termed LipidSens, significantly suppressed tumor growth and induced ferroptosis in cell-derived xenograft mouse models without systemic toxicity. Together, these findings establish MUFA synthesis blockade and PUFA enrichment as a tumor-targeted, ferroptosis-enhancing strategy, and offer a nanomedicine-based therapeutic platform for high-risk NB.</p>

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Dual lipid modulation overcomes ferroptosis resistance in high-risk neuroblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Ine Koeken,
  • Magali Walravens,
  • Roberto Fernández-Acosta,
  • Ruben Van Hoyweghen,
  • Iuliana Vintea,
  • Yingyi Kong,
  • Bianka Golba,
  • Jonas Dehairs,
  • Ali Talebi,
  • Johannes V. Swinnen,
  • Kaat Durinck,
  • Adriana Mañas,
  • Shinya Toyokuni,
  • Gerben Menschaert,
  • Maria Fedorova,
  • Bruno G. De Geest,
  • Behrouz Hassannia,
  • Tom Vanden Berghe

摘要

Ferroptosis—an iron-dependent form of cell death triggered by phospholipid peroxidation—has emerged as a promising therapeutic avenue in cancer treatment. Although neuroblastoma (NB) has been identified as a ferroptosis susceptible cancer, our studies reveal striking heterogeneity in ferroptosis sensitivity across high-risk NB models. Through a targeted metabolic compound screen, we identified stearoyl-CoA desaturase 1 (SCD1)—a key enzyme in monounsaturated fatty acid (MUFA) synthesis—as a robust ferroptosis-sensitizing target. Genetic and pharmacological inhibition of SCD1 restored ferroptosis sensitivity in resistant NB cells. Notably, high SCD1 expression correlates with poor patient prognosis. Co-treatment with arachidonic acid (AA), a polyunsaturated fatty acid (PUFA), further enhanced ferroptotic cell death via increased PUFA/MUFA ratio. Nevertheless, neither baseline lipidomic profiles nor transcriptomes of key ferroptosis regulators reliably predicted ferroptosis sensitivity. To overcome AA’s poor solubility, we engineered AA-loaded lipid nanoparticles (AA-LNPs), which selectively accumulated in high-risk NB tumors and synergized with SCD1 inhibition. This dual-sensitization strategy, termed LipidSens, significantly suppressed tumor growth and induced ferroptosis in cell-derived xenograft mouse models without systemic toxicity. Together, these findings establish MUFA synthesis blockade and PUFA enrichment as a tumor-targeted, ferroptosis-enhancing strategy, and offer a nanomedicine-based therapeutic platform for high-risk NB.