Notably, we found significantly activated NPY receptor activity with substantially higher Y5R expression in matched brain metastatic tumors in contrast to primary tumors, or other NPY receptors or metastatic breast and melanoma cancers and this was significantly correlated with low BMI, resulting in lower brain metastasis-free survival in a Y5R/MAPK-dependent mechanism, indicating that MAPK1 serves as a key oncogenic driver contributing to the downstream effect of NPY in cancer cells. Here, NPY is linked to neoplasm.