Endogenous Cu(II)-binding tripeptide (cosmetic ingredient / skin-regeneration research)

GHK-Cu

Also Known As: Glycyl-L-histidyl-L-lysine copper(II) complex, Cu-GHK, Copper Tripeptide-1, Tripeptide-1 (free GHK), GHK, Liver cell growth factor, Growth-modulating peptide, Kollaren, Prezatide copper acetate, Iamin, Lamin

GHK is an endogenous tripeptide glycyl-L-histidyl-L-lysine that Loren Pickart isolated in 1973 from human plasma albumin (Nature New Biology 243:85–87) as the active fraction that allowed aged hepatocytes to synthesise proteins like young hepatocytes. In solution, free GHK chelates Cu(II) with a high stability constant (log K ≈ 16), forming the 1:1 GHK·Cu²⁺ complex ("GHK-Cu") in which copper sits in a square-planar coordination geometry and is redox-silenced. Endogenous plasma GHK declines, according to the Pickart group, from ~200 ng/mL at age 20 to ~80 ng/mL at age 60. The regulatory framing is unambiguous: GHK-Cu is registered with the INCI dictionary as "Copper Tripeptide-1" and regulated under the U.S. Federal Food, Drug, and Cosmetic Act as a cosmetic ingredient — there is no FDA drug approval. The historical pharmaceutical form prezatide copper acetate (Iamin / Lamin gel, Procyon Pharmaceuticals → Skin Biology) reached only early-phase clinical evaluation and was never granted an FDA new-drug approval; its USAN/INN status is now inactive. All mechanistic statements here distinguish explicitly between free GHK (C₁₄H₂₄N₆O₄, MW 340.38 g/mol, CAS 49557-75-7) and the 1:1 GHK·Cu²⁺ complex (C₁₄H₂₂CuN₆O₄, MW ~401.9 g/mol, CAS 89030-95-5), because the primary literature is not always careful about the distinction.

Identity & Chemistry

Two-dimensional skeletal chemical structure of the GHK-Cu complex showing copper(II) coordinated by the glycyl–histidyl–lysine tripeptide via the glycine α-amino group, the deprotonated peptide-bond amide nitrogen, and the histidine imidazole nitrogen, with the lysine side chain extending free.
Image credit: Edgar181, via Wikimedia Commons · Public Domain (PD-chem; chemical structural formula)
Amino Acid Sequence
H-Gly-His-Lys-OH (free tripeptide GHK; one-letter code GHK; PubChem CID 342538). The "GHK-Cu" most commonly sold and tested is the 1:1 GHK·Cu²⁺ complex in which Cu(II) is coordinated by the glycine α-amino nitrogen, the deprotonated peptide-bond amide nitrogen, and the histidine imidazole nitrogen, with the lysine side chain extending free (PubChem CID 378611).
Molecular Formula
C₁₄H₂₄N₆O₄ (free tripeptide GHK; PubChem 342538) + C₁₄H₂₂CuN₆O₄ (1:1 GHK·Cu²⁺ complex, the form generally credited with dermatological / matrix-remodelling activity; PubChem 378611). The historical pharmaceutical form prezatide copper acetate (Iamin / Lamin gel; DrugBank DB14683) is the 2:1:2 GHK·Cu·acetate stoichiometry C₃₂H₅₄CuN₁₂O₁₂ (PubChem 9876021).
Molecular Weight
340.38 g·mol⁻¹ (free tripeptide GHK; free-base form) + ~401.9 g·mol⁻¹ (1:1 GHK·Cu²⁺ complex). Vendor-supplied research-grade material is typically a lyophilised powder; the blue-violet aqueous reconstitution colour reflects the Cu(II) chromophore.
CAS Number
49557-75-7 (free tripeptide GHK); 89030-95-5 (1:1 GHK·Cu²⁺ complex, "Copper Tripeptide-1"); 130120-57-9 (prezatide copper acetate, the historical 2:1:2 pharmaceutical form / Iamin)
PubChem CID
378611
DrugBank ID
DB14683
IUPAC Name
(2S)-6-amino-2-{[(2S)-2-[(2-aminoacetyl)amino]-3-(1H-imidazol-4-yl)propanoyl]amino}hexanoic acid (free tripeptide GHK). The 1:1 GHK·Cu²⁺ complex is named systematically as the square-planar Cu(II) chelate of glycyl-L-histidyl-L-lysinate.
Solubility
Free GHK is highly water-soluble (≈131 g/L). The GHK·Cu²⁺ complex is soluble in water; reconstituted aqueous solutions appear blue-violet owing to the Cu(II) chromophore. In serum-containing media, free GHK rapidly chelates Cu(II) from the albumin pool (stability constant log K ≈ 16, higher than albumin's high-affinity Cu site).
Storage
Lyophilised peptide stored at −20 °C protected from light. Reconstituted solutions kept at 2–8 °C, light-protected. For topical cosmetic studies, low use-concentrations are typically prepared fresh on site. For research use only.

Mechanism of Action

GHK-Cu is a copper-delivery vehicle and a broad transcriptional modulator: in Connectivity-Map analyses, studies report that GHK significantly modulates ≈32% of human genes (≥50% change threshold), with coordinated up-regulation of DNA-repair, antioxidant, and ubiquitin-proteasome gene sets and down-regulation of pro-inflammatory and metastatic-cancer programmes. There is no single canonical receptor; biological activity is mediated by chelated copper bioavailability and by gene-expression effects observable at nanomolar peptide concentrations.

Loren Pickart isolated GHK in 1973 from human plasma albumin as the active fraction that allowed aged hepatocytes to synthesise proteins like young hepatocytes, publishing the discovery in Nature New Biology (Pickart & Thaler 1973, PMID 4349963), with a synthetic-tripeptide confirmation report in Biochem Biophys Res Commun (PMID 4356974) the same year. Subsequent work — by the Pickart group and several independent dermatology, biochemistry, and biophysical-chemistry teams — established that GHK chelates Cu(II) with a stability constant high enough (log K ≈ 16) to outcompete albumin's high-affinity Cu site, producing a square-planar GHK·Cu²⁺ complex in which copper is redox-silenced. Endogenous plasma GHK declines from ≈200 ng/mL at age 20 to ≈80 ng/mL at age 60, which the Pickart laboratory has proposed as a partial mechanistic explanation for age-related decline in tissue regenerative capacity (Pickart et al. 2012, OMCL). Modern transcriptomic analyses using Connectivity-Map data report that GHK significantly modulates ≈32% of human genes (≥50% change threshold), including coordinated up-regulation of DNA-repair, antioxidant, and ubiquitin-proteasome gene sets and down-regulation of pro-inflammatory and metastatic-cancer gene programmes (Pickart et al. 2014, BMRI). Editorial convention: each mechanistic finding above explicitly names whether it was demonstrated with free GHK (copper supplied by serum) or with the pre-formed GHK·Cu²⁺ complex, because the primary literature does not always disambiguate.

Molecular Targets

  • Collagen, dermatan sulphate, chondroitin sulphate and decorin synthesis — stimulated in dermal fibroblasts at 1–10 nM (GHK-Cu) (Pickart & Margolina 2018, IJMS)
  • TGF-β1 superfamily signalling — restored in COPD-derived fibroblasts; required for proper collagen remodelling (Pickart et al. 2015, BioMed Res Int)
  • MMP / TIMP balance — modulation of matrix metalloproteinases AND TIMP-1 / TIMP-2; regulation of extracellular-matrix turnover
  • Integrin pathways (ITGB4, integrin-β1, integrin-α1) — increased expression in basal keratinocytes; associated with p63⁺ stemness
  • Antioxidant / Nrf2-ARE-related genes — 14 antioxidant genes upregulated (TLE1 +762%, ITGB4 +609%); pro-oxidant TNF / IL17A suppressed (Pickart et al. 2014, BioMed Res Int)
  • DNA-repair machinery — 47 DNA-repair genes stimulated, 5 suppressed; PARP3 +253%, POLM +225%, MRE11A +212%
  • Copper redox silencing — Cu(II) bound in the GHK·Cu²⁺ complex is redox-silenced relative to free Cu²⁺, enabling intracellular copper delivery without Fenton-type oxidative damage (Pickart et al. 2012, OMCL)

Signaling Pathways

  • Improved collagen, decorin, and glycosaminoglycan synthesis in dermal fibroblasts in vitro (free-GHK mediated in serum-containing medium, or as the pre-formed GHK·Cu²⁺ complex)
  • Gene-expression modulation per Connectivity-Map analyses: coordinated up-regulation of DNA-repair, antioxidant, and UPS genes; down-regulation of pro-inflammatory and metastatic-cancer programmes
  • Pro-angiogenic / pro-regenerative effects in wound-healing and hair-follicle models — associated with reduced caspase-3 activity and a Bcl-2/Bax shift toward survival

Research Applications

The evidence base is dual: a rich cosmetic / dermatology literature (Pickart-Margolina reviews, Leyden 2002 facial-photodamage RCT, CIR-2018 safety review, Pyo 2007 hair follicle ex vivo) supports the cosmetic-ingredient positioning, while the therapeutic-drug literature is sparse — the historical INN prezatide copper acetate (Iamin) never reached FDA new-drug approval. As of May 2026, a single Phase 2 GHK-Cu-as-intervention trial is recruiting (NCT07437586, Hudson Biotech, acute punch-biopsy wound healing).

Dermal wound healing — rat / mouse / rabbit / pig, in vivo

in vivo

Studies report that topical GHK-Cu accelerated full-thickness wound healing across multiple species and acted systemically at distant sites; collagen dressings impregnated with GHK in healthy rats produced an approximately 9-fold increase in collagen deposition vs control dressings. Diabetic and ischaemic-wound rat models showed reduced TNF-α and stimulated collagen synthesis with GHK-Cu treatment.

— Pickart & Margolina 2018, IJMS; Pickart et al. 2015, BioMed Res Int

Facial photodamage — human RCT (Leyden 2002, AAD presentation)

observational

Studies report that 67–71 women (aged 50–59) with mild-to-advanced facial photodamage applied a GHK-Cu cream twice daily for 12 weeks; outcomes included improved skin laxity, clarity, firmness, reduced fine lines, coarse wrinkles and mottled pigmentation; ultrasound skin-density and histology showed enhanced dermal keratinocyte proliferation. In a comparative collagen-induction study, GHK-Cu cream produced new collagen formation in 70% of treated subjects vs 50% for vitamin-C cream and 40% for retinoic acid.

— Leyden et al. 2002 (AAD), reported in Pickart & Margolina 2018, IJMS

Hair growth — human hair follicle ex vivo (Pyo et al. 2007)

in vitro

Studies report that the tripeptide-copper complex in cultured human hair follicles increased hair-shaft elongation and dermal papilla cell proliferation ex vivo, reduced caspase-3 activity by ≈42.7%, and shifted the Bcl-2/Bax ratio toward survival.

— Pyo et al., Arch Pharm Res 2007;30(7):834–839

Antioxidant / DNA-repair / gene-expression modulation (Connectivity-Map analyses)

in vitro

Studies report that GHK quenches lipid-peroxidation by-products 4-hydroxy-2-nonenal (4-HNE) and acrolein; Connectivity-Map analyses showed 47 DNA-repair genes upregulated vs 5 suppressed, and suppression of 70% of 54 metastatic-colon-cancer over-expressed genes at 1 µM (in-vitro findings, not clinically validated).

— Pickart et al. 2014, BMRI; Pickart et al. 2012, OMCL

Clinical Status

Regulatory Status
GHK-Cu is NOT an FDA-approved drug. It is registered with the INCI dictionary as "Copper Tripeptide-1" and regulated as a cosmetic ingredient under the U.S. Federal Food, Drug, and Cosmetic Act, which does not require pre-market approval for cosmetics. The Cosmetic Ingredient Review (CIR) Expert Panel reviewed Tripeptide-1, Hexapeptide-12 and their metal salts in 2018 and concluded they are "safe as used" at typical low cosmetic use concentrations (Johnson et al. 2018, IJT). The historical pharmaceutical form prezatide copper acetate (Iamin / Lamin gel, Procyon Pharmaceuticals → Skin Biology) reached only early-phase clinical evaluation and was never granted an FDA new-drug approval; the former USAN/INN status is now inactive in current WHO listings (DrugBank DB14683). A single live GHK-Cu-as-intervention study is registered as of May 2026: NCT07437586 (Hudson Biotech, Phase 2, acute punch-biopsy wound healing, n=60, recruiting). Editorial note: NCT05932732 (a HydraFacial three-treatment study, Austin Institute for Clinical Research) is NOT a GHK-Cu-as-intervention trial and has been explicitly excluded from this page's trial list.
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Highest Trial Phase
Highest active phase as a GHK-Cu monotherapy intervention: Phase 2 (NCT07437586, Hudson Biotech, acute punch-biopsy wound healing, recruiting May 2026). Historically, the former drug form prezatide copper acetate (Iamin gel) reached only early-phase clinical evaluation without FDA approval.
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Sponsor
Current Phase 2 study: Hudson Biotech (NCT07437586). Historical pharmaceutical development: Procyon Pharmaceuticals and later Skin Biology (prezatide copper acetate / Iamin / Lamin gel; INN status inactive). There is no marketing-authorisation holder; GHK-Cu is investigational as a drug and INCI-listed as a cosmetic ingredient.
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Key Clinical Trials

  • Phase 2 randomized double-blind vehicle-controlled split-wound study of topical GHK-Cu (Copper(II)-Peptide Complex) gel 0.1% in healthy adult acute punch-biopsy wounds (Hudson Biotech, recruiting May 2026)
    Phase II
    NCT07437586

Safety Profile

Observed in research settings

For topical cosmetic use at typical use concentrations, the CIR Expert Panel concluded "safe as used" based on negative repeat-dose, skin-irritation, sensitisation, and genotoxicity data (Johnson et al. 2018, IJT). For systemic high-dose research use, a copper-overload caveat must be observed — observed in research / cosmetic-evaluation settings.

Adverse Events Reported in Studies

  • Mild transient erythema or local stinging at the application site has been described in some hair and facial cosmetic studies; serious adverse events were not reported in the Leyden 2002 facial-photodamage cohort (Pickart & Margolina 2018, IJMS)
  • In Pyo 2007 hair-follicle ex-vivo work, no follicle-level cytotoxicity was reported at active concentrations
  • CIR-2018 reviewed available genotoxicity data and found no signal of concern at cosmetic use concentrations

Serious Adverse Events

  • Copper toxicity caveat at high systemic doses: human therapeutic systemic doses are estimated by Pickart et al. at ~75–200 mg, roughly 300-fold below the toxic copper threshold; editorial copy must retain the caveat that systemic high-dose use raises copper-overload concerns (especially for Wilson's-disease patients) and that no validated dosing is established for human therapeutic use (Pickart et al. 2012, OMCL)
  • Pregnancy / lactation: NOT publicly disclosed; no controlled human pregnancy data reported in the cited reviews
  • Drug interactions: no formal human interaction studies publicly disclosed; theoretical caution with chelating agents and copper-restricted regimens

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. 1973 .

    PMID: 4349963 View Source

  2. Pickart L, Thayer L, Thaler MM A synthetic tripeptide which increases survival of normal liver cells, and stimulates growth in hepatoma cells Biochemical and Biophysical Research Communications 1973;54(2):562–566. 1973 .

    DOI: 10.1016/0006-291X(73)91459-9 PMID: 4356974 View Source

  3. Pickart L, Vasquez-Soltero JM, Margolina A The human tripeptide GHK-Cu in prevention of oxidative stress and degenerative conditions of aging: implications for cognitive health Oxidative Medicine and Cellular Longevity 2012;2012:324832. 2012 .

    DOI: 10.1155/2012/324832 PMID: 22666519 View Source

  4. Pickart L, Vasquez-Soltero JM, Margolina A GHK and DNA: resetting the human genome to health BioMed Research International 2014;2014:151479. 2014 .

    DOI: 10.1155/2014/151479 PMID: 25302294 View Source

  5. 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. 2015 .

    DOI: 10.1155/2015/648108 PMID: 26236730 View Source

  6. 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. 2018 .

    DOI: 10.3390/ijms19071987 PMID: 29986520 View Source

  7. Pyo HK, Yoo HG, Won CH, Lee SH, Kang YJ, Eun HC, Cho KH, Kim KH The effect of tripeptide-copper complex on human hair growth in vitro Archives of Pharmacal Research 2007;30(7):834–839. 2007 .

    DOI: 10.1007/BF02978835 PMID: 17703735 View Source

  8. Johnson W Jr, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG, Shank RC, Slaga TJ, Snyder PW, Gill LJ, Heldreth B Safety assessment of tripeptide-1, hexapeptide-12, their metal salts and fatty acyl derivatives, and palmitoyl tetrapeptide-7 as used in cosmetics International Journal of Toxicology 2018;37(3 suppl):90S–102S. 2018 .

    DOI: 10.1177/1091581818807863 View Source

Frequently Asked Questions

Is GHK-Cu approved by the FDA?
No. GHK-Cu is NOT an FDA-approved drug. It is registered with the INCI dictionary as "Copper Tripeptide-1" and regulated as a cosmetic ingredient under the U.S. Federal Food, Drug, and Cosmetic Act, which does not require pre-market approval for cosmetics. The historical pharmaceutical form prezatide copper acetate (Iamin) reached only early-phase clinical evaluation and was never granted an FDA new-drug approval.
What is the difference between GHK and GHK-Cu?
"GHK" refers to the free tripeptide glycyl-L-histidyl-L-lysine (C₁₄H₂₄N₆O₄, MW 340.38, CAS 49557-75-7). "GHK-Cu" refers to the 1:1 complex of GHK with Cu²⁺ (C₁₄H₂₂CuN₆O₄, MW ≈ 401.9, CAS 89030-95-5), the form generally credited with the dermatological and tissue-remodelling activities. In aqueous solution containing serum or any Cu²⁺ source, free GHK rapidly chelates copper, so the in-vivo distinction blurs — but in vitro, mechanistic claims should specify which form was tested.
Is GHK-Cu the same as Argireline or Matrixyl?
No. Argireline is the trade name for acetyl hexapeptide-3 (also called acetyl hexapeptide-8), a synthetic six-amino-acid peptide that acts on SNARE proteins to reduce muscle micro-contraction. Matrixyl is palmitoyl pentapeptide-4, a lipid-conjugated pentapeptide that signals collagen synthesis with no copper involvement. GHK-Cu, by contrast, is a copper-binding tripeptide that signals collagen / matrix synthesis and gene-expression modulation. Different sequences, different mechanisms, different targets.
Does GHK-Cu stimulate hair growth?
Pre-clinical and ex-vivo studies (notably Pyo et al. 2007 in cultured human hair follicles) report that the tripeptide-copper complex enlarges follicle size and reduces dermal papilla cell apoptosis. There are no large, randomized, placebo-controlled human RCTs of GHK-Cu monotherapy on hair growth currently published, so claims should be framed as "preclinical / mechanistic evidence suggests" rather than a proven clinical effect.
Is GHK-Cu safe to use on skin?
The Cosmetic Ingredient Review Expert Panel (Johnson et al. 2018, IJT) concluded that Tripeptide-1 (GHK), its metal salts including the copper complex, and related sequences are "safe as used" in cosmetics at typical use concentrations. Mild local irritation has been reported. Systemic high-dose use raises theoretical copper-overload concerns and is not validated.
When was GHK discovered?
GHK was discovered in 1973: Loren Pickart isolated the active fraction from human plasma albumin and published the finding in Nature New Biology 243:85–87 (PMID 4349963), followed by a synthetic-tripeptide confirmation report in Biochem Biophys Res Commun the same year (PMID 4356974). This makes GHK one of the earliest characterised endogenous human peptide growth-modulators; its copper-binding chemistry was described over the following decades.

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