Dual effects of erastin on aggressive osteosarcoma cells: ferroptosis sensitization and anti-ferroptotic gene activation.

Abstract

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 VDAC2. Furthermore, erastin induces elevated levels of SLC7A11 and SLC3A2, but downregulation of TFRC and HMOX1 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.

Supplementary information: The online version contains supplementary material available at 10.1007/s10616-025-00795-7.