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.