Collectively, these findings reveal the bidirectional plasticity of the ferroptosis regulatory network: targeted inhibition of pro-survival compensatory pathways (e.g., the PERK-ATF4-HSPA5 axis) or activation of pro-death signaling (e.g., the SIRT1-ATF3 axis) can overwhelm tumor cell antioxidant defenses by amplifying oxidative stress, offering a dual intervention strategy of “enhancing pro-death signals” and “blocking negative feedback” to optimize ferroptosis-based glioma therapies. Here, ATF3 is linked to central nervous system cancer.