Fig. 3. Ferroptosis. Ferroptosis is characterised by iron-induced lipid peroxidation.

The intracellular concentration of iron can be affected by the activity of transferrin, transferrin receptor and ferroportin, or by the release of iron from ferritin, which is often managed by ferritinophagy. HNSCC cells often manifest an increased intracellular iron concentration due to a high level of TFRC1 (transferrin receptor 1 responsible for cellular iron uptake) and a low abundance of ferroportin (responsible for iron efflux). The non-physiological degree of lipid peroxidation and the initiation of ferroptosis is prevented by glutathione and glutathione peroxidase 4 (GPX4) activity. Ferroptosis could be also prevented with chelating agents or vitamin E, which casts a bad light on the benefits of antioxidants in the treatment of some ferroptosis-prone cancers. Glutamine and glutaminolysis also play a crucial role in the activation of ferroptosis. PI3KCA is among the most frequently mutated and activated genes in HNSCC. PIK3CA activation can lead to increased mTOR activity and decreased autophagy. Consequently, the presence of PI3KCA activation may predispose these cancer cells to avoid autophagy, ferritinophagy and ferroptosis. The ferroptotic signalling pathways are significantly influenced by HPV infection and by the genetic background of HNSCC. Green bubbles indicate activation and pink inhibition of the process.