Glycyl L histidyl L lysine, complexed with copper(II) as GHK-Cu, is a naturally occurring tripeptide first identified in human serum by Loren Pickart in 1973 [1]. Plasma concentrations decline from approximately 200 ng/mL at age 20 to around 80 ng/mL by age 60, a decline that has been linked to reduced tissue remodelling capacity with age [2].
The 4000 Gene Finding
The most striking modern data on GHK come from the Broad Institute Connectivity Map (CMAP) project, which profiled gene expression changes in human cells exposed to thousands of bioactive molecules. Pickart and colleagues analysed the GHK signature and reported that GHK changed the expression of 31.2% of human genes by 50% or more, increasing expression in 59% of these and suppressing it in 41% [2]; a 2015 review describes this as up- and downregulation of at least 4,000 human genes [3].
The affected pathways include DNA repair, antioxidant defence, ubiquitin proteasome activity, integrin signalling, fibroblast growth, and neurotrophic signalling [2]. This breadth, rather than any single mechanism, may help explain why a three amino acid peptide produces effects across such a wide range of tissues.
Tissue Remodelling and Skin: The Original Evidence
GHK-Cu accelerates wound contraction, increases dermal collagen and glycosaminoglycan synthesis, and improves angiogenesis at wound sites [2]. Animal studies in rabbits, rats, mice, pigs, and dogs have reported faster wound healing, more blood vessel formation and higher antioxidant enzyme levels, and in rats improved healing of diabetic and ischaemic wounds with lower TNF-alpha [3].
Nerve and Neurological Effects
In rats with sciatic nerve injury, collagen nerve guides incorporating GHK (alongside other cell-adhesive peptides in the same study) increased local production of nerve growth factor and the neurotrophins NT-3 and NT-4, with proliferating Schwann cells, during early regeneration [4]. CMAP analysis identified GHK as a candidate compound for reversing gene expression patterns associated with metastatic colon cancer and chronic obstructive pulmonary disease, illustrating that its activity is not confined to skin tissue [5,6].
Anti Inflammatory and Antioxidant Activity
GHK-Cu reduces pro inflammatory cytokines including TNF alpha and IL-6 in animal models, blocks the formation of reactive oxygen and carbonyl species, detoxifies toxic products of lipid peroxidation, and in laboratory tests completely blocked copper-dependent oxidation of low density lipoproteins [2,7]. Copper is also a cofactor for superoxide dismutase and several other antioxidant enzymes.
Bone, Lung, and Stomach Tissue
Reviews also describe improved tissue repair in bone, lung connective tissue, liver and stomach lining [2], and in mice with bleomycin-induced lung injury, GHK attenuated pulmonary fibrosis [8]. The common thread across tissues may be GHK's effect on extracellular matrix remodelling and stem cell activity [7] rather than tissue specific receptors.
Why Copper Matters
Free GHK is biologically active on its own: GHK with and without copper affects large numbers of genes, and GHK alone improved wound contraction in rabbits [2]. The peptide binds copper(II) with an affinity similar to that of the copper transport site on albumin and can take copper from it [3], and early work proposed that GHK acts by facilitating copper uptake into cells [9]. Most of the wound-healing literature uses the copper complex, which is why research grade material is commonly supplied as GHK-Cu rather than as the free peptide.
Limitations of the Current Evidence
Despite extensive in vitro and animal data, large randomised controlled trials in humans for non cosmetic indications are absent. Most human evidence concerns topical cosmetic applications. Researchers should treat extrapolation from gene expression data and animal models to human therapeutic outcomes with appropriate caution.
Research Procurement Considerations
- Confirm material is supplied as the GHK-Cu copper complex, not free peptide
- HPLC purity not less than 99% with mass spectrometry confirmation
- Stoichiometric copper content verified, typically by ICP-MS or atomic absorption
- Storage protected from light and moisture; reconstituted solutions are oxidation sensitive
References
- [1] Pickart L, Thaler MM. "Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver." Nat New Biol. 1973;243(124):85-87. PubMed 4349963
- [2] Pickart L, Margolina A. "Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data." Int J Mol Sci. 2018;19(7):1987. PubMed 29986520
- [3] Pickart L, et al. "GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration." Biomed Res Int. 2015;2015:648108. PubMed 26236730
- [4] Ahmed MR, et al. "Initial upregulation of growth factors and inflammatory mediators during nerve regeneration in the presence of cell adhesive peptide-incorporated collagen tubes." J Peripher Nerv Syst. 2005;10(1):17-30. PubMed 15703015
- [5] Hong Y, et al. "A 'metastasis-prone' signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics." Clin Exp Metastasis. 2010;27(2):83-90. PubMed 20143136
- [6] Campbell JD, et al. "A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK." Genome Med. 2012;4(8):67. PubMed 22937864
- [7] Pickart L, Vasquez-Soltero JM, Margolina A. "GHK-Cu may Prevent Oxidative Stress in Skin by Regulating Copper and Modifying Expression of Numerous Antioxidant Genes." Cosmetics. 2015;2(3):236-247. DOI 10.3390/cosmetics2030236
- [8] Zhou XM, et al. "GHK Peptide Inhibits Bleomycin-Induced Pulmonary Fibrosis in Mice by Suppressing TGFβ1/Smad-Mediated Epithelial-to-Mesenchymal Transition." Front Pharmacol. 2017;8:904. PubMed 29311918
- [9] Pickart L, et al. "Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells." Nature. 1980;288(5792):715-717. PubMed 7453802