Iron-driven regulation of nucleotide synthesis reveals metabolic vulnerabilities in colorectal cancer

In colorectal cancer (CRC), dysregulated iron metabolism alters iron homeostasis, promoting tumorigenesis and cancer progression. Elevated iron levels in the tumor microenvironment facilitate cancer cell proliferation and survival by enhancing DNA synthesis and repair mechanisms. Our previous work demonstrated that transferrin receptor (TFRC)-mediated iron accumulation in CRC cells boosted nucleotide synthesis and tumor growth, contributing to genomic instability. In this study, we identified a correlation between TFRC and metal-dependent nucleotide synthesis enzymes, including ribonucleotide reductase (RNR), phosphoribosyl pyrophosphate amidotransferase (PPAT), and carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD). CRC cells treated with either iron or an iron chelator exhibited altered expression of these three enzymes, indicating that iron modulates their expression and activity. Genetic knockdown of PPAT and CAD disrupted nucleotide metabolism, decreased acetyl-CoA levels, and reduced tumor growth in vitro and in vivo . Interestingly, acetate, a precursor for acetyl-CoA synthesis, rescued acetyl-CoA levels and tumor growth inhibited by the knockdown of either PPAT or CAD. Furthermore, FDA-approved, clinically used nucleotide synthesis inhibitors, teriflunomide and 6-mercaptopurine, effectively reduced colon tumor growth. These findings suggest that understanding the relationship between iron metabolism and nucleotide synthesis in CRC could reveal novel therapeutic targets to inhibit cancer cell proliferation by disrupting iron homeostasis and nucleotide production pathways.