PCSK1 encodes prohormone convertase 1/3 (PC1/3), a serine endoprotease essential for processing peptide hormone precursors at dibasic cleavage sites 1. This enzyme catalyzes the biosynthetic maturation of critical neuroendocrine substrates including proopiomelanocortin (POMC), proinsulin, proglucagon, and ghrelin—peptides fundamental to regulating food intake, glucose homeostasis, and energy balance 12. PCSK1 is localized to secretory granules of endocrine and enteroendocrine cells, where it performs proteolytic processing central to peptide hormone signaling 2. Recent computational approaches have identified additional PCSK1-processed peptides with bioactive properties, including a novel anti-obesity peptide (BRP) that reduces food intake independent of major obesity pathways 3. Disruption of PCSK1 causes rare monogenic obesity and a complex endocrinopathy syndrome characterized by severe early-onset obesity, malabsorptive diarrhea, hypogonadism, and glucose dysregulation 41. Common PCSK1 polymorphisms associate with increased population-level obesity risk and elevated circulating proinsulin levels 15. The FDA-approved obesity therapeutic setmelanotide targets the melanocortin pathway downstream of PCSK1 deficiency, representing a translational success from genetic discovery to clinical treatment 6. Hypothalamic neurons expressing PCSK1 are significantly enriched for genome-wide association study signals for body mass index, confirming its central role in appetite control 7.