Skin hyperpigmentation resulting from excessive tyrosinase expression has long been a problem for beauty lovers, which has not yet been completely solved. Although researchers are working on finding effective tyrosinase inhibitors, most of them are restricted, due to cell mutation and cytotoxicity. Therefore, functional foods are developing rapidly for their good biocompatibility. Food-derived peptides have been proven to display excellent anti-tyrosinase activity, and the mechanisms involved mainly include inhibition of oxidation, occupation of tyrosinase’s bioactive site and regulation of related gene expression. For anti-oxidation, peptides can interrupt the oxidative reactions catalyzed by tyrosinase or activate an enzyme system, including SOD, CAT, and GSH-Px to scavenge free radicals that stimulate tyrosinase. In addition, researchers predict that peptides probably occupy the site of the substrate by chelating with copper ions or combining with surrounding amino acid residues, ultimately inhibiting the catalytic activity of tyrosinase. More importantly, peptides reduce the tyrosinase expression content, primarily through the cAMP/PKA/CREB pathway, with PI3K/AKT/GSK3β, MEK/ERK/MITF and p38 MAPK/CREB/MITF as side pathways. The objective of this overview is to recap three main mechanisms for peptides to inhibit tyrosinase and the emerging bioinformatic technologies used in developing new inhibitors.

The aim of this study was to investigate the anti-melanogenic effects and underlying mechanisms of PFRMY (Pro-Phe-Arg-Met-Tyr), a pentapeptide derived from tilapia skin (Oreochromis niloticus), using B16F10 murine melanoma cells. Treatment with PFRMY (1.0 mg/mL) significantly reduced intracellular melanin content and tyrosinase (TYR) activity by 39.55 ± 1.51% and 32.46 ± 1.31%, respectively. RT-PCR and Western blotting analyses revealed that PFRMY suppressed melanogenesis through the α-MSH/PKA/CREB signaling pathway. Notably, PFRMY reversed α-MSH-induced upregulation of key downstream factors including PKA, CREB, MITF, and TYR, while showing minimal effects on the protein expression of MC1R or α-MSH. Molecular docking further suggested that PFRMY binds to MC1R with higher affinity than α-MSH, potentially occupying the ligand-binding site and thereby interfering with downstream signaling. Collectively, these findings demonstrate that PFRMY effectively inhibits melanogenesis by competitively antagonizing the α-MSH/MC1R axis, highlighting its potential as a safe and efficacious ingredient for hyperpigmentation treatment and cosmetic applications.