A synthetic tripeptide which increases survival of normal liver cells, and stimulates growth in hepatoma cells

Founding article by Loren Pickart — researcher who discovered the GHK (glycyl-histidyl-lysine) tripeptide in human plasma in 1973 and dedicated the following five decades to characterizing it. This specific work, published in BBRC, describes the chemical synthesis of GHK and confirmation of its biological activity in hepatic cell systems — paralleling a simultaneous Nature New Biology publication that described the activity of the form isolated from plasma.

The biological context is historic: Pickart, then a postdoctoral researcher at UCSF with Thaler, observed that plasma from young donors, when applied to aged hepatic tissue in culture, restored that tissue's ability to produce proteins characteristic of young tissue. After extensive biochemical fractionation, he isolated a small tripeptide responsible for the activity, with sequence Gly-His-Lys (GHK). Chemical synthesis of the peptide confirmed the proposed structure and functional equivalence to the endogenous compound.

Biological assays showed that synthetic GHK at nanomolar concentration increased the survival of normal hepatocytes isolated from regenerating rat liver and stimulated the growth of a cultured hepatoma cell line. The tripeptide also stimulated incorporation of labeled uridine and thymidine into TCA-precipitable material, indicating activation of RNA and DNA synthesis. These findings established GHK as a small, well-defined cellular growth factor, opening a new class of bioactive peptide molecules.

Decades after this work, GHK would be recognized in its GHK-Cu form (copper-complexed), with effects on wound healing, collagen and elastin synthesis, and gene expression regulation. The variant palmitoyl-GHK (Pal-GHK, palmitoyl tripeptide-1) was subsequently developed by Sederma as a cosmetic ingredient to stimulate dermal matrix synthesis via lipophilic penetration through the stratum corneum. This 1973 article is the obligatory historical scientific basis for any subsequent work on GHK, GHK-Cu or Pal-GHK — and by extension, for much of modern research on cosmetic peptides.