Monounsaturated fatty acids promote cancer radioresistance by inhibiting ferroptosis through ACSL3

Radioresistance is a major challenge in tumor radiotherapy and involves in a mixture of cellular events, including ferroptosis, a new type of programmed cell death characterized by the excess accumulation of iron-dependent lipid peroxides. In the present study, we observed that surviving cancer tiss...

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Veröffentlicht in:Cell death & disease Jg. 16; H. 1; S. 184 - 13
Hauptverfasser: Cao, Yulin, Li, Jiuming, Chen, Ying, Wang, Yuanben, Liu, Zhiang, Huang, Liuying, Liu, Bingxin, Feng, Yuyang, Yao, Surui, Zhou, Leyuan, Yin, Yuan, Huang, Zhaohui
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 18.03.2025
Springer Nature B.V
Nature Publishing Group
Schlagworte:
13/51
14/28
631/67/395
64/60
692/699/67/1059/2326
692/699/67/1059/485
692/699/67/1504/1885/1777
82/58
82/80
82/81
Animals
Antibodies
Antitumor activity
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cancer
Cell Biology
Cell Culture
Cell death
Cell Line, Tumor
Coenzyme A Ligases - genetics
Coenzyme A Ligases - metabolism
Fatty acids
Fatty Acids, Monounsaturated - metabolism
Fatty Acids, Monounsaturated - pharmacology
Female
Ferroptosis
Ferroptosis - drug effects
Ferroptosis - radiation effects
Glutathione
Humans
Imidazole
Immunology
Life Sciences
Lipids
Long-Chain-Fatty-Acid-CoA Ligase
Mice
Mice, Nude
Neoplasms - metabolism
Neoplasms - pathology
Neoplasms - radiotherapy
Oleic acid
Oleic Acid - pharmacology
Palmitoleic acid
Phospholipids
Piperazines - pharmacology
Polyunsaturated fatty acids
Radiation therapy
Radiation Tolerance - drug effects
Radioresistance
Reactive oxygen species
Reactive Oxygen Species - metabolism
Tumors
ISSN:2041-4889, 2041-4889
Online-Zugang:Volltext
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Zusammenfassung:Radioresistance is a major challenge in tumor radiotherapy and involves in a mixture of cellular events, including ferroptosis, a new type of programmed cell death characterized by the excess accumulation of iron-dependent lipid peroxides. In the present study, we observed that surviving cancer tissues and cells after radiotherapy had significantly greater glutathione to oxidized glutathione (GSH/GSSG) ratios and lower lipid reactive oxygen species (ROS) and malondialdehyde (MDA) levels than nonirradiated tumors and cells. Untargeted lipidomic analyses revealed that oleic acid (OA) and palmitoleic acid (POA) were the most significantly upregulated unsaturated fatty acids in irradiated surviving cancer cells compared with those in control cancer cells irradiated with IR. Both OA and POA could protect cancer cells from the killing effects of the ferroptosis inducer erastin and RSL3, and OA had a stronger protective effect than POA, resulting in lower lipid ROS production than POA. Mechanistically, OA protected cells from ferroptosis caused by the accumulation of polyunsaturated fatty acid-containing phospholipids in an ACSL3-dependent manner. A mouse model demonstrated that ACSL3 knockdown combined with imidazole ketone erastin synergistically enhanced antitumor effects in radiation-resistant tumors in vivo. Our study reveals previously undiscovered associations between radiation and fatty acid metabolism and ferroptosis, providing a novel treatment strategy for overcoming cancer radioresistance.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-025-07516-0