Fig. 3

Mechanisms governing ferroptosis by radiotherapy, chemotherapy, and immunotherapy. A The canonical GPX4-regulated pathway, the iron metabolism pathway, and the lipid metabolism pathway are the three pathways that start the process of ferroptosis and chemotherapy resistance reversal. The canonical GPX4-regulated pathway is regulated as follows: Directly inhibit GPX4 via increasing miR-324-3p, decreasing AR and KIF20A, inhibiting GSH production with ent-kaurane diterpenoids, and blocking cystine absorption with erastin and sorafenib, miR-375, and ATF3. The iron metabolism pathway is regulated as follows: DHA increases cellular LIP while repressing DMT1 and LCN2. The lipid metabolism pathway is regulated as follows: Target LOX by decreasing miR-522 and ACSL4 by decreasing ARF6. B T cells that have been stimulated by immunotherapy treatments release interferon (IFN), which causes ferroptosis. IFN- may reduce tumor cells' ability to take up cystine, which reduces the effectiveness of intracellular GPX4. C There were four phases in the mechanism of radiotherapy-induced ferroptosis. First, radiotherapy impairs system XC transport via ATM, which in turn impacts GSH production. Second step: By increasing ACSL4 expression, radiotherapy encourages lipid production. Third step: By generating DNA damage, radiotherapy triggers autophagy-dependent ferroptosis. Fourth step: Radiation therapy makes it easier for RT-MPs to be made, which leads to lipid peroxidation in nearby cells