Dual lipid modulation overcomes ferroptosis resistance in high-risk neuroblastoma Article Swipe
Ine Koeken
,
Ruben Van Hoyweghen
,
Iuliana Vintea
,
Yingyi Kong
,
Bianka Golba
,
Jonas Dehairs
,
Johannes V. Swinnen
,
Kaat Durinck
,
Adriana Mañas
,
Shinya Toyokuni
,
Gerben Menschaert
,
Tom Vanden Berghe
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1038/s41418-025-01623-3
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1038/s41418-025-01623-3
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.
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- Language
- en
- Landing Page
- https://doi.org/10.1038/s41418-025-01623-3
- https://www.nature.com/articles/s41418-025-01623-3.pdf
- OA Status
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- 46
- OpenAlex ID
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https://openalex.org/W4416715455Canonical identifier for this work in OpenAlex
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https://doi.org/10.1038/s41418-025-01623-3Digital Object Identifier
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Dual lipid modulation overcomes ferroptosis resistance in high-risk neuroblastomaWork title
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articleOpenAlex work type
- Language
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enPrimary language
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2025Year of publication
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2025-11-26Full publication date if available
- Authors
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Ine Koeken, Ruben Van Hoyweghen, Iuliana Vintea, Yingyi Kong, Bianka Golba, Jonas Dehairs, Johannes V. Swinnen, Kaat Durinck, Adriana Mañas, Shinya Toyokuni, Gerben Menschaert, Tom Vanden BergheList of authors in order
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https://doi.org/10.1038/s41418-025-01623-3Publisher landing page
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https://www.nature.com/articles/s41418-025-01623-3.pdfDirect link to full text PDF
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hybridOpen access status per OpenAlex
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https://www.nature.com/articles/s41418-025-01623-3.pdfDirect OA link when available
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| abstract_inverted_index.NB | 41, 78, 139 |
| abstract_inverted_index.To | 123 |
| abstract_inverted_index.as | 12, 26, 176 |
| abstract_inverted_index.by | 8 |
| abstract_inverted_index.in | 17, 36, 57, 76, 137, 158 |
| abstract_inverted_index.of | 4, 71, 115 |
| abstract_inverted_index.we | 49, 128 |
| abstract_inverted_index.NB. | 189 |
| abstract_inverted_index.and | 68, 141, 155, 173, 181 |
| abstract_inverted_index.for | 187 |
| abstract_inverted_index.has | 23 |
| abstract_inverted_index.key | 55, 116 |
| abstract_inverted_index.nor | 113 |
| abstract_inverted_index.our | 31 |
| abstract_inverted_index.via | 104 |
| abstract_inverted_index.(NB) | 22 |
| abstract_inverted_index.MUFA | 170 |
| abstract_inverted_index.PUFA | 174 |
| abstract_inverted_index.SCD1 | 72, 82, 144 |
| abstract_inverted_index.This | 146 |
| abstract_inverted_index.acid | 60, 92, 97 |
| abstract_inverted_index.been | 24 |
| abstract_inverted_index.cell | 5, 102 |
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| abstract_inverted_index.high | 81 |
| abstract_inverted_index.poor | 86, 126 |
| abstract_inverted_index.with | 85, 90, 143 |
| abstract_inverted_index.(AA), | 93 |
| abstract_inverted_index.death | 6, 103 |
| abstract_inverted_index.fatty | 59, 96 |
| abstract_inverted_index.lipid | 131 |
| abstract_inverted_index.mouse | 161 |
| abstract_inverted_index.offer | 182 |
| abstract_inverted_index.these | 167 |
| abstract_inverted_index.tumor | 153 |
| abstract_inverted_index.which | 134 |
| abstract_inverted_index.(MUFA) | 61 |
| abstract_inverted_index.AA’s | 125 |
| abstract_inverted_index.across | 39 |
| abstract_inverted_index.avenue | 16 |
| abstract_inverted_index.cancer | 18 |
| abstract_inverted_index.cells. | 79 |
| abstract_inverted_index.enzyme | 56 |
| abstract_inverted_index.growth | 154 |
| abstract_inverted_index.models | 162 |
| abstract_inverted_index.ratio. | 107 |
| abstract_inverted_index.reveal | 33 |
| abstract_inverted_index.robust | 64 |
| abstract_inverted_index.termed | 149 |
| abstract_inverted_index.tumors | 140 |
| abstract_inverted_index.(PUFA), | 98 |
| abstract_inverted_index.Genetic | 67 |
| abstract_inverted_index.Through | 43 |
| abstract_inverted_index.cancer, | 30 |
| abstract_inverted_index.emerged | 11 |
| abstract_inverted_index.further | 99 |
| abstract_inverted_index.induced | 156 |
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| abstract_inverted_index.neither | 109 |
| abstract_inverted_index.patient | 87 |
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| abstract_inverted_index.studies | 32 |
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| abstract_inverted_index.blockade | 172 |
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| abstract_inverted_index.enhanced | 100 |
| abstract_inverted_index.findings | 168 |
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| abstract_inverted_index.profiles | 112 |
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| abstract_inverted_index.xenograft | 160 |
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| abstract_inverted_index.pharmacological | 69 |
| abstract_inverted_index.polyunsaturated | 95 |
| abstract_inverted_index.tumor-targeted, | 178 |
| abstract_inverted_index.Ferroptosis—an | 1 |
| abstract_inverted_index.dual-sensitization | 147 |
| abstract_inverted_index.nanomedicine-based | 184 |
| abstract_inverted_index.peroxidation—has | 10 |
| abstract_inverted_index.ferroptosis-enhancing | 179 |
| abstract_inverted_index.ferroptosis-sensitizing | 65 |
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