Alpha-MSH

Alpha-MSH (α-Melanocyte-Stimulating Hormone) is an endogenous tridecapeptide derived from POMC (pro-opiomelanocortin). It is a non-selective agonist at melanocortin receptors MC1R–MC5R, driving skin pigmentation via melanogenesis and exerting potent anti-inflammatory effects through central and peripheral pathways. Synthetic analogs include afamelanotide (melanotan I) and melanotan II.

α-MSH binds melanocortin receptors with highest affinity at MC1R (Ki ≈ 0.23 nM), activating Gs-protein signaling and increasing intracellular cAMP. At melanocytes, cAMP activates MITF transcription factor, upregulating tyrosinase and inducing melanin synthesis. At immune cells, α-MSH suppresses NF-κB activation, reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and promoting anti-inflammatory pathways. MC4R signaling in the hypothalamus mediates appetite suppression and energy homeostasis effects.

Extensive preclinical and clinical research demonstrates α-MSH's dual role in pigmentation and immunomodulation. Studies show significant anti-inflammatory effects in models of colitis, arthritis, and uveitis. The synthetic linear analog afamelanotide is FDA-approved for erythropoietic protoporphyria. Research also explores α-MSH in neuroprotection, ischemia-reperfusion injury, and fever regulation. Melanotan II (cyclic analog) has been widely studied for tanning and sexual function but is not approved for human use.

Peptides commonly paired with Alpha-MSH for synergistic effects.