Given the involvement of CYB561 in neuropeptide synthesis and its observed upregulation in CRPC and NEPC, we characterized CYB561 gene expression pattern across different PCa tumor subtypes and PCa cell lines, explored the androgen-dependence of CYB561 expression, demonstrated a role for CYB561 in neuropeptide synthesis and iron metabolism of CRPC, and more importantly, established the contribution of CYB561 to the transdifferentiation and maintenance of the highly aggressive NE phenotype in CRPC. This evidence concerns the gene NPS and posterior cortical atrophy.