Cao Yulin, Li Jiuming, Chen Ying, Wang Yuanben, Liu Zhiang, Huang Liuying, Liu Bingxin, Feng Yuyang, Yao Surui, Zhou Leyuan, Yin Yuan, Huang Zhaohui
Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China.
Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
Cell Death Dis. 2025 Mar 18;16(1):184. doi: 10.1038/s41419-025-07516-0.
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.
放射抗性是肿瘤放射治疗中的一个主要挑战，涉及一系列细胞事件，包括铁死亡，这是一种新型的程序性细胞死亡，其特征是铁依赖性脂质过氧化物过度积累。在本研究中，我们观察到，与未接受放疗的肿瘤组织和细胞相比，放疗后存活的癌组织和细胞的谷胱甘肽与氧化型谷胱甘肽（GSH/GSSG）比值显著更高，脂质活性氧（ROS）和丙二醛（MDA）水平更低。非靶向脂质组学分析显示，与接受IR照射的对照癌细胞相比，油酸（OA）和棕榈油酸（POA）是照射后存活的癌细胞中上调最显著的不饱和脂肪酸。OA和POA都可以保护癌细胞免受铁死亡诱导剂erastin和RSL3的杀伤作用，且OA的保护作用比POA更强，导致脂质ROS产生低于POA。从机制上讲，OA以ACSL3依赖的方式保护细胞免受含多不饱和脂肪酸的磷脂积累引起的铁死亡。小鼠模型表明，ACSL3基因敲低与咪唑酮erastin联合使用可协同增强体内抗辐射肿瘤的抗肿瘤作用。我们的研究揭示了辐射与脂肪酸代谢和铁死亡之间以前未被发现的关联，为克服癌症放射抗性提供了一种新的治疗策略。
