GHK-Cu

GHK-Cu is a naturally occurring tripeptide-copper complex that can enhance tissue repair, anti-inflammatory, antioxidant, and wound-healing activities. It is most popularly known for its use in the cosmetic industry, where it is used to improve the health of skin and reduce signs of ageing, although its application extends beyond this, and it is currently also being investigated for additional medical uses.

Mechanism of Action

GHK-Cu exerts its activity by:

• Improving epithelial repair and upregulating tight junctions: The ability of the body to repair the mucous membrane and tight-junction proteins is hampered by STAT3 activity, a protein that, when persistently activated, is linked to inflammation and diseases such as cancer and autoimmune disease. GHK-Cu activates and upregulates SIRT1, an enzyme that regulates the function of other proteins by deacetylating them, reducing the activity of STAT3. GHK-Cu exhibits additional anti-inflammatory activity even when STAT3 is silenced, indicating that it also influences other anti-inflammatory pathways [1].
• Reducing inflammation and protecting tissues: The elevated or chronic activation of NFκB and MAPK signalling pathways is associated with inflammation and disease. GHK-Cu suppresses MAPK and NFκB-mediated inflammation in certain tissues, decreasing inflammatory cytokines and reactive oxygen species (ROS) and increasing superoxide dismutase (SOD) activity [2].
• Reducing collagen deposition: In chronic fibrosis, TGF-β/Smad persistently signals, which leads to fibrosis and contributes to the progression of cancer. GHK-Cu down-regulates TGF-β1 and inhibits Smad2/3 activation. GHK-Cu can therefore attenuate processes involved in fibrosis and cancer metastasis [3].
• Increasing the activation of antioxidant genes: Nrf2 regulates antioxidant and detoxification genes and can protect against oxidative stress in chronic diseases [4]. The controlled delivery of copper by GHK-Cu is hypothesised to activate Nrf2, which in turn promotes the expression of genes that help to mitigate oxidative damage.

Therapeutic Potential

Studies have investigated the application of GHK-Cu in several therapeutic areas, including:

• Wound healing: Since GHK-Cu can reduce inflammation and enhance the repair of tissues, it is useful in wound healing applications. In tests on animal models, wounds showed faster contraction, better epithelialisation, more granulation tissue, and higher antioxidant enzyme activity [5,6]. In models of diabetes, wounds were found to heal faster, with lower TNFα and MMP-2/9 and increased collagen [7,8].
• Anti-ageing and cosmetic applications: GHK-Cu increases collagen and elastin production and enhances keratinocyte proliferation, increasing skin thickness, elasticity, and hydration [6]. In human trials involving women with photoaged skin, it increased skin density and thickness, decreased laxity, improved firmness and clarity, and reduced fine lines and wrinkle depth [9]. Another trial found that it reduced wrinkle volume by 55.8% and wrinkle depth by 32.8% [10].
• Lung health: It has demonstrated lung-protective activities in animal models of fibrotic lung disease, COPD, acute lung injury, and asthma, where it was found to reduce inflammation and fibrosis [2,11–13].
• Cognition and neurodegeneration: In animal models, it enhanced resilience to brain ageing [14] and delayed the cognitive impairment, amyloid plaques, and inflammation associated with Alzheimer’s [15]. Its effects on gene expression have been mapped and found to influence genes involved in neuronal development, maintenance, and synaptic function [9,16,17]. In models of brain injury, it helped recovery by reducing oedema, improving the survival of neurons, and reducing inflammation [18,19].

Safety

Most studies on GHK-Cu are preclinical, so there is limited data on its safety in humans. Based on results from studies on animal models and humans, GHK-Cu appears to be generally safe. It has demonstrated low skin irritability when applied topically, both with and without microneedle-assisted delivery. It has also been used directly on wounds to promote healing without causing any significant toxicity [20,21].

How It Compares to Pal-GHK

GHK-Cu is the tripeptide GHK complexed with a copper ion, while Pal-GHK is the GHK peptide bound to a palmitoyl group.

The purpose of forming the copper complex, GHK-Cu, is to enhance activity. GHK that occurs naturally in the body has a high affinity for copper and is involved in the binding and safe transport of copper throughout the body, where it is used by cells and enzymes as a cofactor. Since copper is essential for the activity of GHK, GHK-Cu is more bioactive than Pal-GHK [9].

The palmitoyl group of Pal-GHK enhances its ability to penetrate the skin, enabling it to pass into deeper layers of the skin when compared to GHK or GHK-Cu [22].

Overall, both Pal-GHK and GHK-Cu are associated with similar biological activities. The main differences between them are their potency and skin penetration, with GHK-Cu being more active and Pal-GHK being better able to deeply penetrate the skin. This makes GHK-Cu well-suited for medical and cosmetic applications where it can be delivered directly to target tissues or with assistive techniques such as microneedling.

Data Sheet

• Application: Research on wound healing, anti-ageing, pulmonary disease, and neuroprotection
• CAS Number: 49557-75-7
• Molecular Weight: 401.91
• Sequence: Gly-His-Lys (Cu2+)
• Chemical Formula: C₁₄H₂₂CuN₆O₄
• Synonyms: Copper Tripeptide-1, Glycyl-L-histidyl-L-lysine Copper Complex, Cu-GHK, GHK-Cu²⁺
• Storage: Keep refrigerated at 2-8°C until use. For long-term storage, keep at -20°C.
• Reconstitution: Reconstitute in sterile water. The reconstituted solution is stable for up to 30 days at 2-8°C.
• Organoleptic Profile: White to off-white lyophilised powder
• Physical Form: Solid

Conclusion

GHK-Cu is a tripeptide with biological activities that make it suitable for applications in wound healing, cosmetics, pulmonary disease, and neurological disease. Most of the tests conducted on this compound are preclinical, with only a few human studies published, which have found it to effectively reduce signs of aging and improve skin health in humans.

References

1. Mao S, Huang J, Li J, et al. Exploring the beneficial effects of GHK-Cu on an experimental model of colitis and the underlying mechanisms. Front Pharmacol. 2025;16:1551843. doi:10.3389/fphar.2025.1551843
2. Park JR, Lee H, Kim SI, Yang SR. The tri-peptide GHK-Cu complex ameliorates lipopolysaccharide-induced acute lung injury in mice. Oncotarget. 2016;7(36):58405-58417. doi:10.18632/oncotarget.11168
3. Ma WH, Li M, Ma HF, et al. Protective effects of GHK-Cu in bleomycin-induced pulmonary fibrosis via anti-oxidative stress and anti-inflammation pathways. Life Sci. 2020;241:117139. doi:10.1016/j.lfs.2019.117139
4. Deng M, Zhang Q, Yan L, et al. Glycyl‐ l ‐histidyl‐ l ‐lysine‐Cu2+ rescues cigarette smoking‐induced skeletal muscle dysfunction via a sirtuin 1‐dependent pathway. J Cachexia Sarcopenia Muscle. 2023;14(3):1365-1380. doi:10.1002/jcsm.13213
5. 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
6. Pickart L, Vasquez-Soltero JM, Margolina A. GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration. BioMed Res Int. 2015;2015:648108. doi:10.1155/2015/648108
7. Yang X, Zhang Y, Huang C, Lu L, Chen J, Weng Y. Biomimetic Hydrogel Scaffolds with Copper Peptide-Functionalized RADA16 Nanofiber Improve Wound Healing in Diabetes. Macromol Biosci. 2022;22(8):e2200019. doi:10.1002/mabi.202200019
8. Canapp SO, Farese JP, Schultz GS, et al. The effect of topical tripeptide-copper complex on healing of ischemic open wounds. Vet Surg VS. 2003;32(6):515-523. doi:10.1111/j.1532-950x.2003.00515.x
9. 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. doi:10.3390/ijms19071987
10. Badenhorst T, Svirskis D, Merrilees M. Effects of GHK-Cu on MMP and TIMP Expression, Collagen and Elastin Production, and Facial Wrinkle Parameters. J Aging Sci. 2016;04(03). doi:10.4172/2329-8847.1000166
11. Ma W hui, Li M, Ma H feng, et al. Protective effects of GHK-Cu in bleomycin-induced pulmonary fibrosis via anti-oxidative stress and anti-inflammation pathways. Life Sci. 2020;241:117139. doi:10.1016/j.lfs.2019.117139
12. Zhang Q, Yan L, Lu J, Zhou X. Glycyl-L-histidyl-L-lysine-Cu2+ attenuates cigarette smoke-induced pulmonary emphysema and inflammation by reducing oxidative stress pathway. Front Mol Biosci. 2022;9. doi:10.3389/fmolb.2022.925700
13. Zhang Q, Liu J, Deng M ming, Tong R, Hou G. Relief of ovalbumin-induced airway remodeling by the glycyl-l-histidyl-l-lysine-Cu2+ tripeptide complex via activation of SIRT1 in airway epithelial cells. Biomed Pharmacother. 2023;164:114936. doi:10.1016/j.biopha.2023.114936
14. Tucker M, Keely A, Park JY, et al. Intranasal GHK peptide enhances resilience to cognitive decline in aging mice. Neuroscience. Preprint posted online November 17, 2023. doi:10.1101/2023.11.16.567423
15. Tucker M, Liao GY, Park JY, et al. Behavioral and neuropathological features of Alzheimer’s disease are attenuated in 5xFAD mice treated with intranasal GHK peptide.
16. Pickart L, Vasquez-Soltero JM, Margolina A. The Effect of the Human Peptide GHK on Gene Expression Relevant to Nervous System Function and Cognitive Decline. Brain Sci. 2017;7(2):20. doi:10.3390/brainsci7020020
17. 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. Oxid Med Cell Longev. 2012;2012(1):324832. doi:10.1155/2012/324832
18. Zhang H, Wang Y, He Z. Glycine-Histidine-Lysine (GHK) Alleviates Neuronal Apoptosis Due to Intracerebral Hemorrhage via the miR-339-5p/VEGFA Pathway. Front Neurosci. 2018;12. doi:10.3389/fnins.2018.00644
19. Zhang H, Wang Y, Lian L, Zhang C, He Z. Glycine-Histidine-Lysine (GHK) Alleviates Astrocytes Injury of Intracerebral Hemorrhage via the Akt/miR-146a-3p/AQP4 Pathway. Front Neurosci. 2020;14. doi:10.3389/fnins.2020.576389
20. Li H, Toh PZ, Tan JY, et al. Selected Biomarkers Revealed Potential Skin Toxicity Caused by Certain Copper Compounds. Sci Rep. 2016;6(1):37664. doi:10.1038/srep37664
21. Li H, Low YSJ, Chong HP, et al. Microneedle-Mediated Delivery of Copper Peptide Through Skin. Pharm Res. 2015;32(8):2678-2689. doi:10.1007/s11095-015-1652-z
22. Park SI, An GM, Kim MG, Heo SH, Shin MS. Enhancement of Skin Permeation of Wrinkle Improvement Peptides GHKs Using Liposomes Containing Skin Penetrating Peptides. J Korean Appl Sci Technol. 2019;36(3):853-865.