Fig. 4: Schematic representation of CatB and its substrates in the core ferroptosis machinery.

Ferroptosis is mainly caused by iron-dependent lipid peroxidation. Free Fe³⁺ forms a complex with extracellular transferrin, which binds to a TfR1 on the cell membrane and forms endosomes that are transported in the cell under endocytosis. In the cell, Fe³⁺ is catalyzed into Fe²⁺ by the enzyme STEAP3. Fe²⁺ can be pumped out through ferroportin which is located on the cell membrane. Excess Fe²⁺ generates ROS through Fenton chemical reaction, leading to the continuous accumulation of lipid ROS within the cell and the eventual development of ferroptosis. ROS can also interact with PUFAs on the lipid membrane to form lipid ROS. When a large amount of lipid ROS accumulates in the cell, it causes ferroptosis. Membrane lipid peroxidation of lysosome increases the permeability of the lysosomal CatB, which is capable to promote mitochondrial ROS production and degrades H3 in the nucleus. ACSL4 acyl-coenzyme A synthetase long chain family member 4, CatB cathepsin B, DMT1 divalent metal ion transporter 1, ETC electron transport chain, H3 histone 3, LOX lysyl oxidase, LPCAT3 lysophosphatidylcholine acyltransferase 3, PUFAs polyunsaturated fatty acids, ROS reactive oxygen species, STEAP3 six-transmembrane epithelial antigen of the prostate, TfR1 transferrin receptor 1.