Novel Therapeutic Savior for Osteosarcoma: The Endorsement of Ferroptosis

Abstract

Ferroptosis has recently been discovered as an iron-dependent and non-apoptotic regulated mechanism of cell death. The induction of ferroptosis in tumor cells improves tumor treatment, making it a current research hotspot. Mechanistically, it starts by lipid peroxidation, iron accumulation, reactive oxygen species (ROS) production, and glutathione deprivation, highlighting novel treatment opportunities for many tumors and neurodegenerative disorders. Several tumor cell lines are resistant to ferroptosis inducers, even when the ferroptosis key enzyme glutathione peroxidase 4 (GPX4) is blocked, indicating that other important elements are also involved in this process. Ferroptosis-suppressor-protein 1 (FSP1) was discovered to be one of these elements in addition to a few others such as ferroptotic gatekeepers like GTP cyclohydrolase 1 (GCH1) and dihydroorotate dehydrogenase (DHODH). Osteosarcoma is the most common primary malignant bone tumor observed most frequently in children and adolescents. Several studies demonstrated that ferroptosis plays a critical role in the treatment of osteosarcoma, in particular drug-resistant osteosarcoma cells. We outlined four primary regulators involved in ferroptosis in this article, reviewed previously published studies of ferroptosis in osteosarcoma to provide covert insights about osteosarcoma treatment, and highlighted several critical issues to point out future research possibilities.

Keywords: BH4; DHODH; FSP1; GCH1; GPX4; drug resistance; ferroptosis; osteosarcoma.

Figure 1

The four current known regulation systems in ferroptosis. Overall, lipid peroxidation in ferroptosis is under control of GPX4-, FSP1-, GCH1-, and DHODH-dependent systems. GPX4 is the most important gatekeeper for ferroptosis and bolstered through the sustainment of GSH and cystine transportation of system Xc^- activation. System Xc^- is composed of two essential subunits, SLC7A11 and SLC3A2. Generally, ferroptosis could be triggered by GPX4 inhibition directly or indirectly. Nonetheless, several cancer cell lines are resistant to GPX4 inhibition through activating additional regulation systems like FSP1/CoQ₁₀ and GCH1/BH4 systems in the cytoplasm. These two independent manners play a critical role in mitigating cellular ferroptosis especially during loss of GPX4. However, the dysfunction of the three abovementioned systems is observed in organelles such as mitochondria. Notably, then the fourth antioxidant system DHODH-mediated ferroptosis protection in mitochondria is revealed. In the inner membrane of mitochondria, DHODH suppresses ferroptosis via the conversion of ubiquinone to ubiquinol that fights against oxidative damage on the phospholipid membrane. A total of four gatekeepers presumably serve as potential targets for the treatment of osteosarcomas. Except the four pathways, other pathways are also important in regulating ferroptosis, such as ACSL4, AMPK-ACC2, and NF2-YAP pathways, which have been known to affect ferroptosis by regulating PUFA metabolism and cellular phospholipid composition. Lipoxygenases (ALOXs) and POR have been known to affect ferroptosis by driving lipid peroxidation, which play opposite roles to GSH-GPX4, FSP1-CoQ10, GCH1-BH4, and DHODH.