MC5R is a G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha-, beta-, and gamma-MSH) and ACTH, peptide products of the POMC precursor. Upon ligand activation, MC5R couples to Gs protein to stimulate adenylate cyclase and cAMP-dependent signaling, with alpha-MSH showing the highest potency among natural melanocortins. The receptor also activates ERK1/2 through a PI3K-dependent mechanism. MC5R is widely distributed across human tissues including adrenal gland, fat cells, kidney, leukocytes, lung, and pituitary, reflecting its diverse physiological roles in immune regulation, temperature homeostasis, and exocrine gland function. MC5R signaling is antagonized by agouti-signaling protein, which exhibits surmountable competitive effects on receptor-mediated cAMP accumulation 1. Recent evidence demonstrates clinical relevance in inflammatory kidney disease: in a mouse model of membranous nephropathy, the selective MC5R agonist PG-901 attenuated proteinuria and glomerulopathy by suppressing complement amplification in podocytes 2. MC5R agonists are also emerging as non-steroidal alternatives for inflammatory eye diseases such as non-infectious uveitis and dry eye disease, offering reduced systemic adverse effects compared to corticotropin-based therapies 3. Pathogenic variants in MC5R have been associated with ocular and systemic developmental abnormalities including colobomatous microphthalmia and 46,XY complete gonadal dysgenesis.