NFATc1-mediated activation of the pentose phosphate pathway and cell cycle dysregulation collectively drive tumor progression.

The pentose phosphate pathway (PPP) supplies abundant reducing equivalents and biosynthetic precursors to support the rapid proliferation of tumor cells. An increased PPP flux is a hallmark of metabolic reprogramming in tumors. Although nuclear factor of activated T-cells c1 (NFATc1) promotes oncogenesis in various cancers, its role in metabolic reprogramming remains unclear. Here, we demonstrate that NFATc1 enhances NAD kinase (NADK) expression, elevating intracellular NADP levels to activate the PPP, thereby boosting proliferation. Furthermore, NFATc1 binds to both the p1 and p2 promoters of MDM2, sustaining its expression, thereby promoting metabolic reprogramming and accelerating cell cycle progression. Finally, we demonstrated that NFATc1 inhibitors suppress colorectal cancer (CRC) growth by targeting the NFATc1/NADK and NFATc1/MDM2 axis and synergize with oxaliplatin. In summary, our findings reveal that targeting NFATc1 simultaneously restricts biosynthetic precursors and impairs cell cycle progression in CRC, suggesting that NFATc1 inhibition is a promising therapeutic strategy.