All together, our study illustrated a new metabolic feature during the lung metastasis of breast cancer, i.e., enhanced nucleotide de novo synthesis regulated by PRPS2 leads to more cGMP formation, consequently activating cGMP-dependent PKG and downstream MEK-ERK signaling pathway to increase the stemness of breast cancer cells and the metastasis (Fig 8). This evidence concerns the gene PRPS2 and breast cancer.