PCSK1 encodes proprotein convertase 1/3, a serine endoprotease essential for processing hormone and neuropeptide precursors at sites containing paired basic amino acids. Its substrates include proopiomelanocortin (POMC), proinsulin, proglucagon, proghrelin, and other peptides that regulate food intake and energy homeostasis. Loss-of-function PCSK1 variants cause monogenic early-onset obesity, typically presenting with severe malabsorption and diarrhea in infancy followed by hyperphagia and obesity 1. Common PCSK1 polymorphisms increase population obesity risk, and genome-wide association studies consistently link the gene to body mass index variation 1. In addition to obesity, homozygous or compound heterozygous PCSK1 mutations produce complex endocrinopathies including hypogonadotropic hypogonadism, thyroid and adrenal dysfunction, impaired glucose homeostasis, and elevated proinsulin-to-insulin ratios 2. Clinically, the FDA approved setmelanotide, a melanocortin-4 receptor agonist, for patients with severe obesity caused by PCSK1 deficiency, representing a major advance in treating this monogenic obesity subtype 3. Recent evidence suggests PCSK1 processing activity also generates bioactive peptides beyond the canonical substrates that may independently modulate body weight 4.