MC2R is a G protein-coupled receptor for adrenocorticotropin (ACTH) that serves as the master regulator of adrenocortical steroid production. Primarily expressed in the adrenal cortex, MC2R requires the accessory protein MRAP for both functional expression and ACTH binding 1. Upon ACTH activation, MC2R couples to Gs protein, triggering adenylate cyclase and activating cAMP-dependent signaling alongside the MAPK and PKA pathways, ultimately driving glucocorticoid synthesis and release including cortisol and corticosterone. MC2R is also essential for fetal and neonatal adrenal development. Pathogenic MC2R variants cause familial glucocorticoid deficiency (FGD) type 1, an autosomal recessive disorder of ACTH insensitivity; MC2R mutations account for approximately 25% of FGD cases, with an additional 20% attributable to MRAP defects 1. Aberrant MC2R expression has been identified in cortisol-secreting primary bilateral macronodular adrenal hyperplasia and unilateral adenomas, contributing to hormone excess 2. Clinically, FGD is managed through glucocorticoid replacement, while ACTH-based therapies including corticotropin, cosyntropin, and corticotropin zinc hydroxide provide supplementary adrenal stimulation in patients with insufficient endogenous ACTH production. Notably, pharmacological development of melanocortin peptides targeting MC1R, MC3R, MC4R, and MC5R—while sparing MC2R—reduces systemic corticosteroid production and adverse effects compared to ACTH-based approaches 3.