GHK-Cu

What GHK-Cu is

GHK-Cu is the copper(II) complex of a naturally occurring tripeptide, glycyl-L-histidyl-L-lysine (Gly-His-Lys, or GHK). The peptide was reported by Loren Pickart and M. Michael Thaler in 1973, isolated from human serum as a factor that prolonged the survival of normal liver cells in culture [1]. In 1980 Pickart and colleagues proposed in Nature that its biological activity might depend on its ability to bind copper and carry it into cells [2], and since then the compound has usually been studied, formulated and sold as the preformed copper complex rather than the free peptide.

The chemistry is simple compared with the lipidated incretin peptides elsewhere on this site. GHK is three residues long, with no non-natural amino acids, no side-chain modification, a free N-terminal amine and a free C-terminal acid. What distinguishes it is the arrangement of donor atoms. Lau and Sarkar's 1981 study of the copper(II)–GHK interaction concluded that at physiological pH a single copper ion is held by the α-amino nitrogen of glycine, the deprotonated amide nitrogen of the glycine–histidine peptide bond and the imidazole nitrogen of histidine, with the lysine side chain outside the primary coordination sphere [3]. The resulting 1:1 complex is highly stable, with a binding constant comparable to that of the copper site on serum albumin, which is why GHK is thought to exchange copper with albumin in plasma [3].

A copper(II) ion coordinated by nitrogen donors absorbs in the visible range, so the lyophilised complex is a blue to blue-violet powder and its solutions are blue, deepening with concentration. The free tripeptide is white and colourless in solution, so a vial of GHK-Cu that is not blue has not been supplied as the complex.

Reference identifiers are in the table below. Suppliers and databases do not all write the formula the same way. The free peptide is C14H24N6O4 (340.4 g/mol). Vendors commonly write the complex as C14H24N6O4Cu, about 403.9 g/mol, which is the free peptide plus a copper atom; the neutral complex with two protons displaced by copper is C14H22CuN6O4 (about 401.9 g/mol), and salt forms such as the acetate carry a different CAS number and mass again. A certificate should state which representation it uses.

How the literature describes its mechanism

There is no single accepted mechanism. The literature proposes three overlapping explanations, and the authors of the main reviews acknowledge that none is complete.

The first is copper delivery. The 1980 Nature paper argued that GHK's effects on cultured cells could be explained by its facilitating copper uptake, and that the activity depended on the metal [2]. Copper is a cofactor for lysyl oxidase, which cross-links collagen and elastin, and for superoxide dismutase, so a small, stable carrier able to hand copper to cells has an obvious route to effects on connective tissue and oxidative stress. Pickart and Margolina's 2018 review states that this hypothesis "is still valid" but does not, in their view, account for the breadth of gene-expression changes reported, which is why they argue for a broader model [11].

The second is direct action on extracellular matrix turnover. Maquart and colleagues in Reims, with Pickart as a co-author, reported in 1988 that GHK-Cu stimulated collagen synthesis in cultured human skin fibroblasts at concentrations down to the nanomolar range [4]. Siméon and colleagues from the same group later reported that it also increased matrix metalloproteinase-2 expression in fibroblast cultures [5]. The reviews frame these as evidence of remodelling rather than simple deposition: both synthesis and controlled breakdown of matrix are increased, the pattern one would want in a healing wound [10, 11]. These are fibroblast monolayer studies from one group, and the response to copper salts alone is a confounder not every study controls for.

The third is gene-expression modulation. Pickart's group used the Broad Institute's Connectivity Map, a public database of transcriptional profiles from human cell lines treated with small molecules [9], to compare the GHK signature against disease signatures. They report that roughly 31% of genes assayed changed by at least 50% in either direction, somewhat more up- than down-regulated, with DNA repair, antioxidant and tissue-remodelling genes among them, and that the GHK signature ran opposite to a published emphysema signature [10, 11]. These are computational comparisons of existing profiles rather than new wet-lab experiments; the Connectivity Map data were generated with the free peptide in cultured cancer cell lines at a single concentration. The findings are useful for hypothesis generation and have not been independently replicated in a form that settles what GHK-Cu does in living tissue.

For an in-vitro programme the relevant readouts are collagen and glycosaminoglycan synthesis in dermal fibroblasts, metalloproteinase and TIMP expression, keratinocyte and fibroblast proliferation, and transcriptomic profiling. Potency figures cluster in the 10⁻¹² to 10⁻⁸ M range, which is unusually low, and the dose–response is often reported as bell-shaped [4, 10]. That shape makes concentration accuracy more important than usual, and is one reason net peptide content and copper content matter on the certificate.

The research record

GHK-Cu has been studied for five decades, but the record is wide rather than deep. Most of it is in vitro, in animal models, or in small cosmetic studies, and much of the primary and review literature carries Pickart's name. That is not a reason to dismiss it, but it is a reason to read it with care about independent replication.

Discovery and plasma concentration. The 1973 paper described a serum fraction that prolonged hepatocyte survival in culture [1]. Pickart's later reviews report that plasma GHK falls with age, from about 200 ng/mL (roughly 10⁻⁷ M) at age 20 to about 80 ng/mL by age 60, and connect this to a loss of regenerative capacity [10, 11]. The figures are quoted widely, but in the 2015 and 2018 reviews they appear without a clearly attached primary citation, and measuring a short peptide in plasma at these concentrations is not trivial. We have not located an independent modern assay confirming them.

Copper chemistry. Lau and Sarkar's work remains the reference description of the complex: coordination mode, 1:1 stoichiometry at physiological pH and affinity relative to albumin [3]. With the 1980 Nature paper on copper uptake [2], this is the most solidly established part of the record, because it is coordination chemistry rather than biology.

Fibroblast and matrix studies. The Reims group's work established the fibroblast effects: collagen synthesis [4], then glycosaminoglycan, metalloproteinase and TIMP expression [5, 10]. These remain the most cited primary sources for GHK-Cu's dermal biology.

Wound healing in animals. The reviews collect studies in rabbits, rats, mice, pigs and dogs reporting faster closure, more collagen, better granulation tissue, higher antioxidant enzyme activity and greater vessel density in treated wounds, including collagen dressings loaded with the complex in healthy and diabetic rats and lower MMP-2, MMP-9 and inflammatory cytokines in ischaemic rat wounds [10, 11]. The same reviews note that GHK-Cu is degraded by carboxypeptidases, which may limit its persistence in a wound [11]. Many of these studies are old, several come from groups with commercial involvement, and the models and endpoints vary too much to aggregate into a single effect size.

Skin studies in people. This is the thinnest part. Abdulghani and colleagues in 1998 compared a copper-peptide cream with vitamin C and tretinoin on thigh skin in a small pilot study, reporting collagen improvement on biopsy in a majority of the copper-peptide group [6]. Other frequently cited results, including the facial and eye cream studies in women with photo-aged skin, exist only as conference abstracts or a book chapter, not as full peer-reviewed papers [11]. Gorouhi and Maibach's 2009 review of topical peptides in ageing skin summarises this literature with appropriate caution [8].

Hair follicles. GHK-Cu is often described as a hair-growth compound, but the primary literature under the GHK-Cu name is sparse. The study usually cited is Pyo and colleagues' 2007 ex vivo work, in which a tripeptide-copper complex elongated cultured human hair follicles and increased dermal papilla cell proliferation at 10⁻¹² to 10⁻⁹ M, with a reduced apoptotic signal at 10⁻⁹ M [7]. That study used AHK-Cu (alanyl-histidyl-lysine copper), a related but distinct complex, not GHK-Cu, and secondary sources frequently conflate the two. The older GHK-Cu hair data are largely from animal work and patents rather than peer-reviewed human studies [10].

Taken together, the record supports GHK-Cu as a well-characterised copper carrier with reproducible effects on fibroblast matrix metabolism in vitro and consistent, if heterogeneous, signals in animal wound models. The human evidence is small, cosmetic and mostly unpublished in full; there are no controlled clinical trials.

Regulatory status in the United Kingdom

GHK-Cu occupies an unusual position because it has a long history as a cosmetic ingredient. Under the INCI name Copper Tripeptide-1 it has been used in creams and serums since the 1990s, regulated as an ingredient of a finished cosmetic under the UK Cosmetics Regulation, with the obligations falling on the responsible person placing that product on the market. That is a different regulatory category from the material sold here.

The GHK-Cu supplied by BuyUK Peptides is a research chemical: a lyophilised powder for in-vitro laboratory use under the Terms of Sale. It is not a cosmetic product, is not a medicine, is not manufactured under a cosmetic safety assessment or a marketing authorisation, and carries no claim about what it does on or in a person. It is not for human or veterinary administration, topical or otherwise. Purchasers must be 18 or over and are responsible for ensuring that their use of the material complies with the laws and institutional rules that apply to them. Our guide to the UK rules on research compounds explains why cosmetic-ingredient status does not transfer to a research chemical.

Handling, storage and stability

GHK-Cu is supplied as a blue lyophilised powder, sealed in a glass vial with a rubber stopper and an aluminium flip-off crimp. The complex is robust for a peptide: it is short, has no oxidation-prone methionine or cysteine, and the copper coordination protects the glycine–histidine amide bond. The main risks are moisture, light and loss of copper to competing chelators.

Sealed vial. Store at 2–8 °C for routine use and at −20 °C for longer storage. Protect from light; copper(II) peptide complexes can undergo slow photochemical change on prolonged exposure. The powder is hygroscopic, so allow a refrigerated vial to reach room temperature before opening to prevent condensation onto the cake.

Solubility and reconstitution. GHK-Cu is highly water-soluble and dissolves almost instantly in water or saline, without the slow wetting seen with larger lipidated molecules. For in-vitro work it is normally reconstituted in sterile water or an assay-appropriate buffer. The reconstitution calculator gives the volume for a target concentration; because activity is reported at nanomolar and picomolar levels, serial dilution from a concentrated stock is the usual practice.

Choice of buffer. This is the point specific to copper peptides. Avoid buffers and additives that chelate copper more strongly than GHK does, or that compete by sheer concentration: EDTA and other aminopolycarboxylates, citrate, and high phosphate, which can precipitate copper phosphate. Tris and HEPES at ordinary strengths are generally tolerated, and PBS at physiological phosphate is used in the literature, but a solution that fades from blue towards colourless, or develops a pale precipitate, has lost copper and is no longer GHK-Cu. Strong reducing agents will also reduce the copper(II) and discharge the colour. In serum-containing medium, remember that albumin competes for the copper with an affinity of the same order as GHK's [3].

Reconstituted solution. Keep solutions at 2–8 °C, protected from light, and use them promptly; suppliers of the acetate salt advise against holding aqueous solutions for more than a day for analytical work, and for cell work it is sensible to prepare fresh dilutions from a frozen stock held in single-use aliquots. A solution that has changed colour or clarity should be discarded.

What a sound certificate for GHK-Cu looks like

Every batch we release carries an independent certificate of analysis, transcribed on the product page and in the certificate register. GHK-Cu is a simple molecule to analyse, but the metal adds items that do not appear on other certificates.

Purity by RP-HPLC. Reversed-phase HPLC with UV detection at 214 or 220 nm reports the main peak as a percentage of all integrated peaks. For a tripeptide the chromatogram is short and simple, and a good batch shows a single dominant peak with purity of 98% or above. Some methods run under conditions, such as low pH with trifluoroacetic acid, that partly dissociate the complex on the column, so what is measured is usually the purity of the peptide rather than of the intact complex. That is acceptable provided the certificate says so and copper content is reported separately.

Identity by LC-MS. Electrospray mass spectrometry should show the free tripeptide, with a protonated mass of about 341.2, and may also show the copper-bound species. The complex and the free peptide have different masses, and copper's two stable isotopes (⁶³Cu and ⁶⁵Cu, roughly 69:31) give the copper-bound peak a characteristic doublet two mass units apart, which is itself a useful identity check. A certificate quoting only 340 or 341 has confirmed the peptide; one that also shows the copper adduct has confirmed the complex. It should state which mass it reports and against which formula.

Copper content or peptide-to-copper ratio. This is the item unique to copper peptides. It may be reported as a weight percentage of copper by ICP-OES, ICP-MS or atomic absorption, or as a molar ratio of peptide to copper. For the 1:1 complex written as C14H24N6O4Cu the theoretical copper content is about 15.7% by mass; a salt or hydrate will be lower. Copper well below theory means a significant fraction of free peptide; well above it means free copper salt, which is cytotoxic in culture and will confound any assay.

Net peptide content and water. Lyophilised peptides carry bound water and counter-ions. GHK-Cu is hygroscopic, so water content by Karl Fischer titration or loss on drying is more informative than for most peptides, and net content is what should be used when calculating molarity.

Endotoxin. Where tested, a limulus amoebocyte lysate result in endotoxin units per milligram is relevant to any cell-based work, particularly for a compound whose claimed effects include modulation of inflammatory gene expression.

Our guide to reading a certificate of analysis walks through a complete report line by line.

Related compounds

GHK-Cu is the parent of a small family of copper-binding tripeptides. AHK-Cu replaces the N-terminal glycine with alanine and is the complex actually used in the 2007 hair follicle study above [7]; our comparison of copper peptides sets out the differences in structure, copper affinity and published evidence. BPC-157 is not a copper peptide but is often studied alongside GHK-Cu in wound and tissue-repair models, with a similar evidence profile: substantial animal data and very little in humans. GHK-Cu is also a component of our Glow blend, supplied with other research peptides for comparative in-vitro work.

Frequently asked questions

Why is the powder blue? Because the copper(II) ion coordinated by the peptide's nitrogen atoms absorbs red and orange light. The free tripeptide is white. Blue colour confirms the material is the complex rather than the free peptide, though it says nothing about purity.

Is this the same substance as the copper peptide in cosmetics? Chemically, yes: Copper Tripeptide-1 is the INCI name for GHK-Cu. Regulatorily, no. A cosmetic ingredient is assessed as part of a finished cosmetic product. The research-grade material sold here is a laboratory chemical and is not for application to the skin or any other human use.

Why does the certificate mass not match the formula weight on the product page? Usually because the mass spectrometer has detected the free peptide (about 340) rather than the complex (about 402 to 404 depending on representation), or because the batch is a salt form. A sound certificate explains which species it is reporting.

Can I use the free peptide and add copper myself? Some published studies do exactly this, but the copper salt, its concentration and the buffer all affect how much complex forms, and free copper is toxic to cells. A preformed complex with measured copper content removes that variable.

How long does a sealed vial last? Short, unmodified peptides are stable for years at −20 °C when kept dry and dark. The batch certificate reports the test date; the storage guidance on this page applies from receipt.

References

1. Pickart L, Thaler MM. Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver. Nature New Biology. 1973;243(124):85–87. PMID 4349963.
2. Pickart L, Freedman JH, Loker WJ, et al. Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells. Nature. 1980;288(5792):715–717. doi:10.1038/288715a0. PMID 7453802.
3. Lau SJ, Sarkar B. The interaction of copper(II) and glycyl-L-histidyl-L-lysine, a growth-modulating tripeptide from plasma. Biochemical Journal. 1981;199(3):649–656. doi:10.1042/bj1990649. PMID 7340824.
4. Maquart FX, Pickart L, Laurent M, Gillery P, Monboisse JC, Borel JP. Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu²⁺. FEBS Letters. 1988;238(2):343–346. doi:10.1016/0014-5793(88)80509-X. PMID 3169264.
5. Siméon A, Emonard H, Hornebeck W, Maquart FX. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu²⁺ stimulates matrix metalloproteinase-2 expression by fibroblast cultures. Life Sciences. 2000;67(18):2257–2265.
6. Abdulghani AA, Sherr A, Shirin S, et al. Effects of topical creams containing vitamin C, a copper-binding peptide cream and melatonin compared with tretinoin on the ultrastructure of normal skin. Disease Management and Clinical Outcomes. 1998;1(4):136–141. doi:10.1016/S1088-3371(98)00011-4.
7. Pyo HK, Yoo HG, Won CH, et al. The effect of tripeptide-copper complex on human hair growth in vitro. Archives of Pharmacal Research. 2007;30(7):834–839. doi:10.1007/BF02978833.
8. Gorouhi F, Maibach HI. Role of topical peptides in preventing or treating aged skin. International Journal of Cosmetic Science. 2009;31(5):327–345. doi:10.1111/j.1468-2494.2009.00490.x. PMID 19570099.
9. Lamb J. The Connectivity Map: a new tool for biomedical research. Nature Reviews Cancer. 2007;7(1):54–60. doi:10.1038/nrc2044. PMID 17186018.
10. Pickart L, Vasquez-Soltero JM, Margolina A. GHK peptide as a natural modulator of multiple cellular pathways in skin regeneration. BioMed Research International. 2015;2015:648108. doi:10.1155/2015/648108. PMID 26236730.
11. Pickart L, Margolina A. Regenerative and protective actions of the GHK-Cu peptide in the light of the new gene data. International Journal of Molecular Sciences. 2018;19(7):1987. doi:10.3390/ijms19071987. PMID 29986520.

This monograph summarises the published literature for laboratory researchers. It is not medical advice, and nothing on this site is for human or veterinary use.