Antioxidant capacity of the iron-sulfur cluster assembly protein IscU2 is mediated by aspartate metabolism to promote tumor survival.

Environmental nutrient levels affect cancer cell metabolism, activating adaptive mechanisms in cancer cells to deal with nutrient stress. However, it remains unclear how tumor cells sustain survival under nutrient-stress circumstances through metabolic reprogramming. Our study focused on nutrient deficiency-induced oxidative damage, revealing that increased expression of the iron-sulfur (Fe-S) cluster assembly protein, IscU2, is essential for the survival of pancreatic ductal adenocarcinoma (PDAC) cells in glucose-deficient conditions. Glucose deficiency induces IscU2 expression via the activation of the AMPK pathway, allowing IscU2 to exhibit antioxidant properties that are absent under glucose-sufficient conditions. Upregulated IscU2 stimulates aspartate synthesis by bolstering mitochondrial metabolism, including respiration and the tricarboxylic acid cycle, in a Fe-S cluster-dependent manner. Notably, oxidative stress and apoptosis induced by IscU2 depletion in glucose-deficient PDAC cells can be restored by aspartate-mediated NADPH production. These findings highlight the importance of IscU2 in PDAC cell metabolism and its essential function in supporting cell survival under nutrient-deficient conditions.