Fig. 3

The mechanisms of RT-induced ferroptosis in tumor cells. Intracellular cystine import is controlled by the cystine/glutamate antiporter (System X_c-), with SLC7A11 being the core component. Inhibition of the SLC7A11-GSH-GPX4 pathway leads to accumulation of lipid peroxides and promotes ferroptosis. Damage to cellular DNA by radiation leads to increased ATM. ATM has been shown to inhibit SLC7A11, reduce cystine import, and promote ferroptosis. Also, p53 activation following DNA damage may play a dual role in the SLC7A11-GSH-GPX4 pathway. On the one hand, p53 can inhibit SLC7A11 transcription and promote ferroptosis; on the other hand, activated p53 can up-regulate p21, maintain GSH levels during stress, and inhibit ferroptosis. During ferroptosis, ACSL4 and LPCAT3 are critical regulators and rate-limiting factors. ACSL4 can catalyze PUFA to generate PUFA-CoA. PUFA-CoA is processed to form lysophospholipids, which are then combined with phospholipids (PLs) by LPCAT3 to form PUFA-PLs. In RT, ROS can act on PUFAs and lead to lipid peroxidation in a dose-dependent manner. In addition, RT can induce ACSL4 expression, promote PUFA-PLs synthesis, and ultimately lead to ferroptosis. ACSL4, acyl-CoA synthetase long-chain 4; Cys2, cystine; ER, endoplasmic reticulum; GGC, γ-Glutamylcysteine; LPCAT3: lysophosphatidylcholine acyltransferase 3; PLOOH, phospholipid hydroperoxide. PUFA, polyunsaturated fatty acid; PUFA-PL, phospholipid containing polyunsaturated fatty acid chain; RT: radiotherapy; SLC7A11: solute carrier family 7 member 11