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doi: 10.1182/blood-2025-6945 142 MaitiAPostSDiNardoCDaverNAlvarado ValeroYOhanianMet al

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CHAC1 further exacerbates cellular stress by degrading GSH, intensifying oxidative damage and ultimately driving ferroptotic cell death (Figure 5) ( FIGURE 5 While the eIF2K3/PERK-eIF2-ATF4 cascade, another branch of the ISR, can modulate ferroptosis in the context of ER stress, cysteine deprivation selectively activates GCN2 rather than PERK, highlighting distinct regulatory mechanisms ( Cysteine starvation triggers mitochondrial fragmentation, impairs mitochondrial function and leads to the accumulation of ROS ( CHAC1 is upregulated through the ATF4-dependent ISR pathway, where it degrades GSH to liberate cysteine needed for the synthesis of Fe-S cluster proteins ( CHAC1 is the most strongly upregulated gene, primarily via the ATF4-dependent ISR pathway

Conclusion and future perspectives Ovarian cancer continues to be the deadliest among gynecological cancers, primarily due to its subtle beginnings, diagnosis at advanced stages, frequent relapses, and inherent resistance to standard chemotherapy treatments

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