Fig. 4: ISR activation rewires central carbon metabolism.

a Heatmap of significant metabolites (FDR q < 0.01) as measured by LC-MS at the indicated time points following addition of dimerizer (0.05 nM) to WT or ATF4 KO Dmr-PERK cells. Relative abundances are shown as row mean centered z-scores. b Heatmap of TCA cycle metabolites from a. c Schematic of incorporation of ¹³C-label from U-¹³C6-glucose into the TCA cycle and in the synthesis of fatty acids. d Bar plots representing fractional labeling of TCA cycle metabolites from U-¹³C6-glucose in WT and ATF4 KO cells treated with vehicle (Veh.) or dimerizer (Dmr, 0.05 nM) for 24 h. Error bars depict mean ± SD of three technical replicates. e Schematic of incorporation of ¹³C-label from U-¹³C5-glutamine from oxidation (blue) vs. reductive carboxylation (red). Bar plots representing fraction labeling of malate, Asn or Asp from oxidative (M + 4) (f) or reductive (M + 3) (g) metabolism of U-¹³C5-glutamine in WT and ATF4 KO cells treated with vehicle (Veh.) or dimerizer (Dmr, 0.05 nM) for 24 h. Error bars depict mean ± SD of three technical replicates. Bar plots representing the fraction of palmitate carbons labeled from U-¹³C5-glutamine (h) or U-¹³C6-glucose (i) in lipids from WT or ATF4 KO Dmr-PERK cells treated with vehicle (Veh.) or dimerizer (Dmr, 0.05 nM) for 24 h. Error bars depict mean ± SD of three technical replicates. Statistical significance was evaluated by two-way ANOVA followed by Tukey’s HSD test. Source data are provided as a Source Data file.