Burns Gordon Daniel, Schneider Kevin, Atilano Shari, Chwa Marilyn, Chang Steven, Kenney M Cristina, Singh Mithalesh Kumar
Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697 USA.
Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA 92697 USA.
Cytotechnology. 2025 Aug;77(4):128. doi: 10.1007/s10616-025-00795-7. Epub 2025 Jun 23.
Osteosarcoma (OS) is a rare cancer, yet the most prevalent primary bone cancer in adolescents and young adults OS can be fatal and detrimental due to its high aggressiveness, early metastases, and chemo-resistance. Recent research suggests that drugs that induce ferroptosis could treat osteosarcoma. It is unknown how erastin-induced ferroptosis influences differential gene expression of System Xc, iron absorption, heme synthesis, and mono- (MUFA) and polyunsaturated (PUFA) fatty acid levels in aggressive OS cells. In this study, we show that erastin-induced ferroptosis decreases OS cell growth and survival by raising total ROS, mitochondrial membrane potential, and downregulating . Furthermore, erastin induces elevated levels of and , but downregulation of and in OS cells. Notably, the addition of Ferrostatin-1 protects against Erastin-induced cytotoxicity, implying that these agents induce ferroptosis. We also showed that Ferrostatin-1 provides partial protection against Erastin-induced ferroptosis by stimulating the unique transcriptional gene profile of System Xc-, MUFA, and PUFA while inhibiting iron uptake and heme production in OS cells. These findings show that Erastin inhibits the survival of aggressive OS cells, but it also increases the expression of genes linked with anti-ferroptosis activity, which could lead to preventing ferroptosis in the aggressive OS phenotype. Targeting this anti-ferroptotic differential gene expression mediated by erastin-induced ferroptosis in OS cells may help to improve erastin's efficacy.
The online version contains supplementary material available at 10.1007/s10616-025-00795-7.
骨肉瘤（OS）是一种罕见的癌症，但却是青少年和年轻成年人中最常见的原发性骨癌。由于其高侵袭性、早期转移和化疗耐药性，骨肉瘤可能是致命的且具有危害性。最近的研究表明，诱导铁死亡的药物可以治疗骨肉瘤。尚不清楚埃拉斯汀诱导的铁死亡如何影响侵袭性骨肉瘤细胞中Xc系统、铁吸收、血红素合成以及单不饱和脂肪酸（MUFA）和多不饱和脂肪酸（PUFA）水平的差异基因表达。在本研究中，我们表明埃拉斯汀诱导的铁死亡通过提高总活性氧水平、线粒体膜电位并下调……来降低骨肉瘤细胞的生长和存活率。此外，埃拉斯汀诱导骨肉瘤细胞中……水平升高，但……和……下调。值得注意的是，添加铁抑素-1可保护细胞免受埃拉斯汀诱导的细胞毒性，这意味着这些药物诱导了铁死亡。我们还表明，铁抑素-1通过刺激Xc系统、MUFA和PUFA的独特转录基因谱，同时抑制骨肉瘤细胞中的铁摄取和血红素生成，为埃拉斯汀诱导的铁死亡提供部分保护。这些发现表明，埃拉斯汀抑制侵袭性骨肉瘤细胞的存活，但也增加了与抗铁死亡活性相关的基因表达，这可能导致侵袭性骨肉瘤表型中铁死亡的预防。针对骨肉瘤细胞中埃拉斯汀诱导的铁死亡介导的这种抗铁死亡差异基因表达，可能有助于提高埃拉斯汀的疗效。
在线版本包含可在10.1007/s10616-025-00795-7获取的补充材料。
