Fig. 2

This diagram illustrates the interconnected pathways involved in ferroptosis. First, the amino acid pathway is crucial for GSH production, a key antioxidant. Cystine enters the cell through the Xc- antiporter, is converted into cysteine, and combines with glutamate and glycine to form GSH. GPX4 then uses GSH to neutralize lipid peroxides, preventing ferroptosis. Second, the lipid pathway shows how PUFAs are processed by enzymes such as ACSL4, LPCAT3, and ALOX15, resulting in the formation of PUFA-OOH, which, if not neutralized by GPX4, triggers ferroptosis. Third, the iron pathway highlights how Fe²⁺ contributes to ferroptosis by generating ROS through the Fenton reaction. Iron enters cells via Tf, is reduced to Fe²⁺ by STEAP3, and either stored in ferritin or exported by FPN1. Excess Fe²⁺ leads to ROS production, enhancing lipid peroxidation and promoting ferroptosis. Lastly, the Nrf2 pathway serves as a protective mechanism against ferroptosis. Nrf2, typically inhibited by Keap1, is released during oxidative stress, translocates to the nucleus, and activates the expression of antioxidant genes like GPX4. This helps mitigate oxidative stress, regulate lipid peroxidation, and control iron metabolism, thereby preventing ferroptosis