@haidut Interesting find -- thankss! Yet another reason to keep the glucose uptake high and to avoid metabolic stess.
From this paper's concluding passages [bold-facing is mine]:
"These results also have implications for therapeutic strategies that
manipulate cyst(e)ine availability. Intracellular cysteine became toxic
at concentrations of approximately 1–1.5 mM (Extended Data Fig. 4l),
substantially above its normal systemic abundance. In fasting human
plasma, free cysteine and cystine are present at approximately 10 µM
and 80 µM, respectively, with total cyst(e)ine reaching ~250 µM (refs.
31,32). Thus, the toxic threshold is unlikely to be reached through bulk plasma exposure but may be approached in cells with unusually high cyst(e)ine uptake or impaired cysteine disposal. One such example would be cancers with constitutive NRF2 activation that accumulate cysteine beyond biosynthetic demand through upregulation of SLC7A11, promoting the formation of cysteine-derived conjugates that may serve as a detoxification route [33]. Cysteine or NAC has also been reported to induce cell death in glioblastoma and other cellular contexts, particularly during metabolic stress¹¹,³⁴. Our study suggests that, when this buffering capacity is exceeded, or under conditions of metabolic stress such as glucose limitation, excess cysteine becomes deleterious. Conversely, cystine supplementation can enhance tissue regeneration and stem-cell function in some settings.³⁵. Such findings are therefore likely to depend on the capacity of the receiving cells to metabolize or safely dispose of the resulting cysteine. Cysteine damages the mitochondrial electron transport chain via iron–sulfur protein loss, leading to cells relying more on glycolysis for ATP production and trying to uptake more glucose (Extended Data Fig. 4b). This would explain why glucose starvation is synthetically lethal with high cyst(e)ine as exemplified by disulfidptosis, although this death cannot be rescued by iron chelation [10]. Although this process shares features with ferroptosis, it occurs despite elevated GSH and suppressed lipid peroxidation, defining a distinct form of mitochondrial iron-dependent cell death (Extended Data Fig. 4m). Together, these results position thiol imbalance as a central metabolic vulnerability and underscore the importance of both limiting cysteine accumulation and promoting its safe disposal to maintain cellular homeostasis. "