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 (Ward et al., 2024)
Moreover, the acidification of the tumor microenvironment due to the secretion of lactate, the final glycolytic product, contributes to cancer cell invasiveness and immune suppression
However, you need to know the details and do your homework because glutathione is a finicky molecule, and not all forms are absorbable
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