GHK-Cu

Technical data

INN name

Copper Tripeptide-1

CAS

89030-95-5

Molecular formula

C14H23CuN6O4

Molecular weight

402.92 g/mol

Identity and composition

GHK-Cu (Glycyl-L-Histidyl-L-Lysine copper(II) ion) is a copper-tripeptide complex with molecular mass 340.85 Da, formed by the GHK sequence (Gly-His-Lys) covalently bound to a divalent copper ion Cu²⁺ with high affinity (dissociation constant Kd ~10⁻¹⁶ M). It was discovered in 1973 by Dr. Loren Pickart como una fracción del plasma humano capaz de devolver al tejido hepático envejecido características de tejido joven.

GHK is a natural fragment of type I collagen, released during tissue remodeling. Its plasma concentration falls with age (from ~200 ng/mL at age 20 to ~80 ng/mL at 60), a correlation that positions it as key biomolecule in wound healing and skin regeneration.

Structure and properties:

• Linear Gly-His-Lys tripeptide of 340 Da.
• The copper coordinates with the imidazole of histidine and the terminal amino groups, forming a square planar complex.
• High aqueous solubility (>10 mg/mL).
• Characteristic blue color due to ligand-to-metal charge transfer (LMCT).
• Estabilidad moderada: sensible a pH alcalino y luz UV.

Unlike newer regenerative peptides (BPC-157, TB-500), GHK-Cu acts simultaneously as a modulator of gene expression and as a vehicle for bioavailable copper, a dual function that defines its unique profile. It is used in dermatological research, experimental cosmetics, wound healing, hair regeneration, and cellular senescence. It has no approval as a systemic medication, although topical cosmetic formulations are marketed internationally.

Mechanism of action

El mecanismo de GHK-Cu es pleiotropic, with two main arms:

1. Broad-spectrum gene expression modulator: estudios transcriptómicos (Pickart et al., Biomed Res Int 2015) muestran que GHK-Cu modula la expresión de more than 4,000 human genes (15% del genoma codificante), reseteando perfiles hacia patrones de tejido joven:

• Al alza: reparación de DNA, respuesta antioxidante (NRF2), síntesis de matriz extracelular (colágeno I, III, IV, decorina, glicosaminoglicanos), antiapoptosis.
• Downregulated: pro-inflammatory genes (TNF, IL-6) and oncogenes (>70% of those evaluated show repression).

2. Bioavailable and catalytic copper carrier: copper is a cofactor of >12 critical human enzymes (lysyl oxidase for collagen cross-linking, cytochrome c oxidase, Cu/Zn superoxide dismutase, tyrosinase, dopamine-β-hydroxylase). GHK-Cu delivers it in a controlled manner, without the toxicity of free copper.

Documented secondary mechanisms:

• Matriz extracelular: stimulates dermal fibroblasts to produce collagen I/III, elastin, glycosaminoglycans (dermatan sulfate), and proteoglycans.
• Angiogenesis: induce VEGF y bFGF en queratinocitos.
• Anti-inflammatory: reduce TNF-α, IL-6, IL-1β; inhibe NF-κB inducido por TGF-β.
• Antioxidant: estimula SOD y catalasa; quela radicales hidroxilo.
• Células madre: increases proliferation of dermal stem cells and hair bulb cells.
• Metaloproteinasas: equilibra MMP-1/MMP-2 con sus inhibidores TIMP.
• Neuroprotection: en modelos de Alzheimer modula β-amiloide e inflamación neural.
• Receptor LRP1: hipótesis emergente de receptor primario.

Diferencia con otros regenerativos: GHK-Cu acts at the transcriptional level, resetting the aging profile; BPC-157 and TB-500 act on signaling cascades (VEGF/NO and actin). Non-redundant mechanisms.

Pharmacokinetics

Formal pharmacokinetic data in humans are limited; most derive from animal and in vitro models.

Topical route (the most studied):

• Penetra el estrato córneo eficientemente por su tamaño pequeño (340 Da).
• Concentración eficaz cosmética: 0.05%–0.5% (250 a 2,500 ppm).
• Acumulación dérmica tras aplicación repetida.

Subcutaneous/intramuscular route:

• Biodisponibilidad alta (>70% estimado en animales).
• Tmax: 15–30 minutes.
• Plasma half-life: 40 minutes to 2 hours.
• Tissue accumulation at sites of active injury.

Oral route: viable parcialmente (absorción vía transportadores PepT1), pero degradación GI significativa; biodisponibilidad sistémica baja (<10%).

Metabolism: degradación proteolítica en glicina, histidina y lisina; el cobre liberado entra al pool corporal.

Elimination/distribución: copper has a prolonged tissue half-life (weeks) in liver, brain and muscle; the tripeptide is cleared rapidly. Broad cutaneous penetration and into hair follicles; modest blood-brain barrier crossing. Degradation by serum peptidases within 1–2 h.

Concentraciones endógenas: ~200 ng/mL en jóvenes, ~80 ng/mL en >60 años, base de la hipótesis de suplementación anti-senescencia.

Scientific evidence

La evidencia se concentra en preclinical models (rat, mouse, rabbit) and dermatological clinical studies con formulaciones tópicas.\n\nSkin healing:\n- Pollard et al. (Arch Facial Plast Surg 2005; PMID 15655171): aumento de la proliferación y de la expresión de factores de crecimiento en fibroblastos normales e irradiados, en cultivo celular.\n- Maquart et al. (FEBS Lett 1988, J Clin Invest 1993): estimulación de síntesis de matriz extracelular en fibroblastos humanos.\n- Úlceras venosas (Mulder et al.): reducción del 64% en área vs control a 12 semanas.\n\nAesthetic dermatology:\n- Leyden et al. (J Cosmet Dermatol 2002): mejora de arrugas, elasticidad e hidratación en mujeres ≥50 años a 12 semanas con crema GHK-Cu 0.1%.\n- Comparado con vitamina C, retinol y α-hidroxiácidos: equivalente o superior en biomarcadores de remodelación dérmica.\n\nHair regeneration: estudios de Procyte Corporation (estimulación folicular en modelos murinos); uso post-trasplante capilar.\n\nTranscriptómica: Pickart et al. (Biomed Res Int 2015): modulación de 4,000+ genes; Hong et al. (Mol Med Rep 2015): represión de genes asociados a cáncer colorrectal.\n\nOtros: neuroprotección (Alzheimer, regeneración axonal), cardiovascular (reducción de necrosis en infarto), pulmonar (EPOC/fibrosis, Campbell et al. 2012).\n\nLimitations: no existen ensayos clínicos sistémicos formales (fase II/III) parenterales; la evidencia humana es mayormente tópica.

Research applications

Cosmetic and reparative dermatology (main use in humans):

• Arrugas, líneas finas, elasticidad, fotoenvejecimiento.
• Cicatrices post-acné, post-quirúrgicas, post-quemadura; estrías.
• Chronic ulcers (venous, pressure, diabetic).
• Post-inflammatory hyperpigmentation.

Hair regeneration:

• Alopecia androgenética inicial; recuperación post-trasplante folicular; alopecia areata (preliminar).

Systemic regenerative research:

• Cicatrización de tendones y ligamentos (animal).
• Post-ischemia recovery (myocardium, brain, renal).
• Senescencia replicativa: extensión de vida útil de cultivos primarios.

Experimental neuroprotection:

• Alzheimer (reducción de placas β-amiloide), lesión medular y nerviosa periférica (regeneración axonal).

Inflammatory modulation: EPOC, fibrosis pulmonar, enfermedad inflamatoria intestinal (limitado).

Vías por aplicación:

• Topical: dermatology, hair, superficial wound healing.
• Subcutaneous: systemic research.
• Intramuscular: regeneración musculoesquelética profunda.
• Intralesional: scars, alopecia areata.
• Mesotherapy: rejuvenecimiento facial y capilar.

All systemic application is research; topical cosmetic use is approved and available in multiple jurisdictions.

Research protocols

Protocols vary by route and objective. Doses are investigational references.

Cosmetic topical (the most documented):

• Concentración: 0.05%–0.5% (250 a 2,500 ppm).
• 1–2 times/day on clean skin; effects visible at 4–8 weeks, continuous maintenance.

Facial mesotherapy:

• 2–5 mg/sesión, microinyecciones intradérmicas.
• 1 vez/semana × 4–6 sesiones, luego mensual.

Systemic subcutaneous (research):

• 1–3 mg/día, diaria o en días alternos, 4–12 semanas.

Regenerative intramuscular:

• 2–5 mg/dosis cerca del sitio de lesión, 2–3 veces/semana.

Capilar (intradérmica de cuero cabelludo):

• 1–2 mg en microinyecciones múltiples, 1 vez/semana × 8–12 semanas.

Animal models (scaling):

• Rat: 0.5–5 mg/kg/day subcutaneous. Human equivalent (factor 6.2): ~5–50 mg for a 70 kg adult in aggressive studies.

Research combinations:

• + BPC-157 (cicatrización cutánea compleja); + TB-500 (regeneración profunda); + Matrixyl (cosmética avanzada); + minoxidil (capilar).

Monitoring sistémico: cobre sérico y ceruloplasmina, función hepática, hemograma.

Reconstitution

Lyophilized GHK-Cu is reconstituted with bacteriostatic water (BAC) for injection, or with cosmetic vehicles for topical use.

Procedimiento (inyectable):

1. Equilibrate vial and solvent to room temperature for 15 min.
2. Clean the stopper with 70% isopropanol.
3. Inject BAC slowly onto the side wall of the vial.
4. Do not shake: gently roll to dissolve in 1–2 minutes.
5. La solución debe ser transparent blue (color del complejo cobre); descartar si hay turbidez o color anómalo.

Reference concentrations:

50 mg vial:

• 1 mL BAC → 50 mg/mL (1 mg = 0.02 mL = 2 IU)
• 2.5 mL BAC → 20 mg/mL (1 mg = 0.05 mL = 5 IU)
• 5 mL BAC → 10 mg/mL (1 mg = 0.1 mL = 10 IU)

100 mg vial:

• 2 mL BAC → 50 mg/mL
• 5 mL BAC → 20 mg/mL (1 mg = 0.05 mL = 5 IU)
• 10 mL BAC → 10 mg/mL (1 mg = 0.1 mL = 10 IU)

Syringe: U-100 insulin syringe of 0.3–1 mL; 30–32G needle for mesotherapy, 29–31G for subcutaneous.

Uso tópico (formulación experimental): base hidrofílica (gel de ácido hialurónico, crema neutra), concentración final 0.1%–0.5%, pH óptimo 5.5–7.0. Excluir ácido ascórbico, α-hidroxiácidos y peróxidos (compiten por cobre).

Calculation: volume (mL) = dose (mg) / concentration (mg/mL).

Stability and storage

Sealed lyophilized vial:

• Store at 2–8 °C, protected from light; stability up to 24 months per manufacturer.
• Tolerates room temperature for up to 30 days.
• Sensible a luz UV: pack in aluminum or amber vial.

Vial reconstituted with BAC:

• Store strictly at 2–8 °C, protected from light; stability 28–30 days preservando actividad.
• No congelar (puede precipitar el complejo cobre). El azul debe mantenerse uniforme; el cambio a verde o incoloro indica disociación del cobre.

Topical formulation: stability 6–12 months in an opaque container with preservatives; airless containers preferable.

Estabilidad química: estable en pH 4–7; degradación rápida en pH alcalino (>8). Incompatible con quelantes fuertes (EDTA) y antioxidantes que reduzcan Cu²⁺ a Cu⁺ (ácido ascórbico). Estable térmicamente hasta 40 °C transitorio.

Degradación: descartar ante cambio de color, turbidez o precipitado; pH fuera de 5–7 reduce actividad.

Transport: cold gel pack; the lyophilized product tolerates 48–72 h at controlled temperature.

Safety profile

GHK-Cu presents a favorable safety profile, especialmente en uso tópico, ampliamente documentado en cosmética internacional.

Topical use (more established profile):

• Irritation: rare at concentrations <0.5%.
• Transient hyperpigmentation from copper: occasional, reversible.
• Sensibilidad al cobre: muy rara (<0.1%); contraindica el uso.
• No documented phototoxicity.

Systemic use (research):

• Toxicidad aguda en animales: LD50 muy alta (>1 g/kg en rata IV).
• Subcrónica: bien tolerado a dosis suprafarmacológicas 30–90 días, sin alteraciones hematológicas, hepáticas ni renales.

Genotoxicity: estudios in vitro negativos; al contrario, reprime oncogenes en transcriptómica, sugiriendo perfil protector.

Carcinogenicity: sin estudios a 2 años, pero el perfil anti-tumoral (represión de >70% de oncogenes) y la ausencia de reportes de inducción tumoral sugieren bajo riesgo.

Copper accumulation: riesgo teórico en uso sistémico prolongado a dosis altas. Contraindicated in Wilson's disease. Monitorear cobre sérico y ceruloplasmina en protocolos largos.

Hypersensitivity: precaución con alergia al níquel (reactividad cruzada teórica); reacciones locales en mesoterapia ocasionales y leves.

Pregnancy and lactation: insufficient data, use not advised as a precaution.

Interactions: incompatible con quelantes de cobre (D-penicilamina, trientina); el zinc alto puede interferir con la absorción de cobre.

WADA status: It is NOT on the prohibited list; permitido en deportistas.

Sitio de inyección: dolor leve, eritema transitorio, ocasional coloración azul-verde local que desaparece en 24–48 h.

Comparative context

vs BPC-157: GHK-Cu modulates gene expression + delivers copper; BPC-157 modulates VEGFR2/NO/wound healing. GHK-Cu dominates in skin/hair/anti-aging and is effective topically; BPC-157 in musculoskeletal/GI and requires injection (or oral GI). They are combined in complex cutaneous wound healing.

vs TB-500: TB-500 acts on G-actin and cell migration, more systemic; GHK-Cu on transcription and matrix, predominantly local/dermatological. Combination documented in tissue regeneration.

vs Matrixyl (palmitoyl pentapeptide-4): Matrixyl stimulates collagen via TGF-β-like signaling; GHK-Cu is broader (anti-inflammatory + antioxidant + matrix). Frequently combined.

vs Retinoides: potentes pero irritantes; GHK-Cu menos irritante, perfiles complementarios.

vs Vitamina C: ambos antioxidantes y pro-colágeno por mecanismos distintos, pero incompatibles: el ácido ascórbico reduce Cu²⁺ a Cu⁺ disociando el complejo. No coformular; alternar aplicaciones.

vs Growth factors (EGF, bFGF): recombinants are more expensive and labile; GHK-Cu is more stable, economical, and broader-spectrum.

vs copper-peptide analogs (AHK-Cu, FOXO4-Cu): AHK-Cu has a similar spectrum with less evidence; GHK-Cu is the most studied of the group.

Ventaja: doble mecanismo, evidencia dermatológica robusta, seguridad establecida, costo accesible, no prohibido por WADA. Disadvantage: lower individual potency in systemic musculoskeletal regeneration vs BPC-157/TB-500.

History and development

GHK-Cu was discovered in 1973 by Dr. Loren Pickart en la Universidad de California San Francisco, al investigar la diferencia entre plasma de donantes jóvenes y mayores: una fracción peptídica del plasma joven restauraba la síntesis proteica en hepatocitos de rata vieja. La fracción activa era el tripéptido GHK unido a cobre.\n\nHitos:\n- 1973: descubrimiento de la actividad biológica de GHK (Pickart).\n- 1980s: caracterización de la unión al cobre y mecanismos básicos.\n- 1988–1993: Maquart et al. (Francia) demuestran estimulación de matriz extracelular en fibroblastos humanos.\n- 1990s: Procyte Corporation comercializa formulaciones cosméticas y de cicatrización (Tricomin®, Iamin®).\n- 2002: Leyden et al. publican estudios clínicos cosméticos.\n- 2005: Pollard et al. publican efectos sobre proliferación y factores de crecimiento en fibroblastos en cultivo.\n- 2015: Pickart et al. publican el análisis transcriptómico (4,000+ genes; Biomed Res Int).\n- 2018–presente: expansión a neuroprotección, aplicaciones pulmonares y regenerativas.\n\nRegulatorio: approved as a cosmetic ingredient in the USA (FDA OTC monograph), EU (CosIng), Japan, Korea, Australia, and Mexico (COFEPRIS). NOT approved as a systemic parenteral medication. Widely available research reagent. WADA: no prohibido.\n\nPatents: Pickart and Procyte filed multiple patents (1980s–1990s) on formulations; the basic molecule is in the public domain. Academia: >150 indexed publications, with active groups in the USA, France, Korea, and China. for research use.

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Scientific references (8)

Peer-reviewed literature on GHK-Cu, with its PubMed identifier when available:

• GHK-Cu in tissue regeneration: new genomic data (Pickart L, Margolina A. · International Journal of Molecular Sciences · 2018) — Broad transcriptomic analysis of the action of GHK-Cu on gene expression in human fibroblasts and keratinocytes. PMID 29986520.
• GHK Peptide as a Natural Modulator of Multiple Cellular Pathways (Pickart L, Margolina A. · BioMed Research International · 2015) — Review of the multiple mechanisms of GHK-Cu in tissue regeneration and anti-aging. PMID 26236730.
• Glycyl-L-histidyl-L-lysine-Cu(2+) rescues cigarette smoking-induced skeletal muscle dysfunction via a sirtuin 1-dependent pathway (Deng, et al. · Journal of Cachexia, Sarcopenia and Muscle · 2023) PMID 36905132.
• Effects of topical copper tripeptide complex on CO2 laser-resurfaced skin. (Miller TR, et al. · Arch Facial Plast Surg · 2006) PMID 16847171.
• Enhanced healing of ulcers in patients with diabetes by topical treatment with glycyl-l-histidyl-l-lysine copper. (Mulder GD, et al. · Wound Repair Regen · 1994) PMID 17147644.
• Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+). (Siméon A, et al. · J Invest Dermatol · 2000) PMID 11121126.
• Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. (Maquart FX, et al. · FEBS Lett · 1988) PMID 3169264.
• In vivo stimulation of connective tissue accumulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ in rat experimental wounds. (Maquart FX, et al. · J Clin Invest · 1993) PMID 8227353.

Otras presentaciones de GHK-Cu

• GHK-Cu Serum 30 mL

Guides and articles about GHK-Cu

Lecturas del blog de EXOMA que la editorial asoció a este compuesto:

• GHK-Cu (Copper Tripeptide): scientific evidence from Pickart 1973 to today
• GHK-Cu: Copper-Tripeptide Mechanism in Dermal Research
• Peptides for the Skin: Anti-Wrinkle, Collagen and Regeneration [2026 Guide]

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