Fuzuloparib enhances radiosensitivity of gain-of-function mutant p53 R273H NSCLC by promoting SLC7A11/GSH/GPX4 axis mediated ferroptosis

Radiotherapy is a crucial therapeutic approach for the management of non-small cell lung cancer (NSCLC). Nevertheless, the radioresistance of NSCLC, particularly in cases involving the gain-of-function mutant p53, substantially limits its efficacy. According to recent research, mutant p53 R273H can recruit poly (ADP-ribose) polymerase (PARP)-1 on replicating DNA to promote tumor survival. Whether mutant p53 R273H-mediated radioresistance is related to the interaction between mutant p53 R273H and PARP1, and if PARP1 inhibitors (PARPi) can increase the radiosensitivity of mutant p53 R273H-expressing tumors have not been explored. Through in vitro and in vivo experiments, we determined that mutant p53 R273H promotes radioresistance in NSCLC by partially inhibiting ferroptosis through the SLC7A11/GSH/GPX4 axis, independently of PARP1, whereas FZ counteracts this effect by partially blocking the same axis to promote ferroptosis, presenting a potential novel strategy for treating NSCLC patients with gain-of-function mutant p53 R273H.