Ferroptosis

Ferroptosis is a non-apoptotic form of regulated cell death. It is distinct from other regulated cell death phenotypes, such as apoptosis and necroptosis. Ferroptosis is an iron- and ROS-dependent form of regulated cell death (RCD). Ferroptosis is characterized by extensive lipid peroxidation, which can be suppressed by iron chelators or lipophilic antioxidants. Mechanistically, Ferroptosis inducers are divided into two classes: (1) inhibitors of cystine import via system xc− (e.g., Erastin), which subsequently causes depletion of glutathione (GSH), and (2) covalent inhibitors (e.g., (1S, 3R)-RSL3) of glutathione peroxidase 4 (GPX4). Since GPX4 reduces lipid hydroperoxides using GSH as a co-substrate, both compound classes ultimately result in loss of GPX4 activity, followed by elevated levels of lipid reactive oxygen species (ROS) and consequent cell death.

Cuproptosis is a newly discovered unique non-apoptotic programmed cell death distinguished from known death mechanisms like ferroptosis, pyroptosis, and necroptosis. It is copper-triggered and mediated by protein lipoylation mainly in mitochondria. Mechanistically, cuproptosis occurs through the direct binding of copper to the lipoylated components of the tricarboxylic acid (TCA) cycle. When respiring, the lipoylated TCA enzymes [particularly the pyruvate dehydrogenase (PDH) complex] increase and result in an abnormal aggregation of lipoacylated proteins and the loss of Fe-S cluster–containing proteins, which leads to inevitably acute proteotoxic stress and ultimately cell death