Fig. 2: G6PD deficiency accelerates ADM and PanIN.

a, Schematic of the PPP. In the first step of glycolysis, glucose is converted into glucose 6-phosphate (glucose 6P). G6PD, the first and rate-limiting enzyme of the oxidative PPP (oxPPP; blue), converts glucose 6P into 6-phosphogluconolactone and NADPH. Another NADPH-producing enzyme in the oxPPP, 6-phosphogluconate dehydrogenase (6PGD), generates ribulose 5-phosphate (ribulose 5P). Ribulose 5P can be used in the nonoxidative PPP (nonoxPPP; green) by the enzymes ribulose-5-phosphate 3-epimerase (RPE) and ribose-5-phosphate isomerase (RPI) to generate intermediate metabolites that enter glycolysis or nucleic acid biosynthesis, including ribose 5-phosphate (ribose 5P). b, H&E staining and immunostaining for amylase (AMY; acinar cells), cytokeratin 19 (CK19; ductal, metaplastic, neoplastic cells) and Ki67 (proliferation) in pancreata from 16-week-old KC;G6pd^wt and KC;G6pd^mut mice. Scale bars, 50 μm. c, Percentage of AMY-positive area in pancreata as quantified from male (closed circles) and female (open circles) KC;G6pd^wt and KC;G6pd^mut mice at 16 weeks; n = 4 mice for each genotype. Bars represent the mean values; error bars, s.d. P values were calculated using a Student’s t-test (unpaired, two-tailed). d,e, Percentage of CK19⁺ cells (d) and Ki67⁺ cells (e) in the pancreas as quantified from male (closed circles) and female (open circles) KC;G6pd^wt and KC;G6pd^mut mice at 16 weeks; n = 5 mice for each genotype. Bars represent the mean values; error bars, s.d. P values were calculated using a Student’s t-test (unpaired, two-tailed). f, H&E staining, Alcian Blue staining (for PanIN-produced mucins) and CK19 (ductal, metaplastic, neoplastic cells) immunostaining in 26-week-old KC;G6pd^wt and KC;G6pd^mut mice. Scale bars, 100 μm. g, Pathological grading of pancreas tissues from 26-week-old KC;G6pd^wt and KC;G6pd^mut mice, representing the percentage of total tissue area with acinar cells, ADM and PanIN lesions; n = 5 KC;G6pd^wt mice; n = 7 KC;G6pd^mut mice. Bars represent the mean values; error bars, s.d. P values were calculated using a two-way ANOVA with Tukey’s post hoc test. h, H&E staining in 1-year-old KC;G6pd^wt and KC;G6pd^mut mice. Scale bars, 100 μm. i, Pathological grading of pancreas tissues from 1-year-old KC;G6pd^wt and KC;G6pd^mut mice, representing the percentage of total tissue area with acinar cells, ADM and PanIN lesions; n = 5 mice for each genotype. Bars represent the mean values; error bars, s.d. P values were calculated using a two-way ANOVA with Tukey’s post hoc test.

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