Figure 3.

Lysosome and ferroptosis. Ferroptosis occurs owing to the imbalance between ROS generation and antioxidant defense system. Iron promotes ROS accumulation by enhancing the enzymetic activity of LOX or through Fenton reaction. But GPX4, coming from increased Cys2, reduces oxidative injury. Lysosome affects ferroptosis via regulating iron homeostasis, CMA (lysosomal degradation of GPX4) or clockophagy (lysosomal degradation of circadian clock protein ARNTL, which facilitates EGLN2 expression, thus destabilizing HIF1A and promoting LPO with subsequent ferroptosis). Lysosome increases the concentration of intracellular active iron, and NCOA4-dependent ferritinophagy is the most important form. Ferritin is sequestered into autophagosomes and then delivered to lysosome for degradation, liberating iron from ferritin. Increased labile iron concentration mediated by ferritinophagy in turn engages the IRP–IRE iron homeostatic system which leads to a continuous increase of ferritin synthesis, thus forming a positive feedback. Moreover, lysosome may also be related to increased transferrin and attenuated ferroportin-1 expression. Cys2: cystine; TFR1: transferrin (TF) receptor 1.