Fig. 1: Metabolic pathways and key molecular mechanisms of ferroptosis.

Initiation and execution of ferroptosis is attributed to accrued intracellular iron that is probably accentuated by ferritinophagy, disrupted mitochondrial function, a depletion of GSH that could result from deranged cysteine transport and GPx4 inactivation. The system x_c⁻ (consisting of two subunits SLC7A11 and SLC3A2) is responsible for redox balance by uptake of extracellular cystine at the exchange of intracellular glutamate at 1:1 molar ratio. Inside the cell, cystine is reduced to cysteine by GSH and subsequently used for biogenesis of GSH. GPx4 is the core GSH utilizing enzyme, and it efficiently represses detrimental LOX overactivation and lipid peroxidation. Low GPx4 activities give rise to elevated accumulation of ROS and consequently to ferroptosis induction. A series of ferroptotic cell death inhibitors and activators have been well established in the past decades that interfere with different upstream events. GSH glutathione, GPx4 glutathione peroxidase 4, SLC7A11 solute carrier family 7 member 11, SLC3A2 solute carrier family 3 member 2, LOX lipoxygenases, ROS reactive oxygen species.