GHK (Copper-Free)
Also known as: Glycyl-L-histidyl-L-lysine, Gly-His-Lys, GHL, copper-free GHK, GHK tripeptide
Not an approved drug; cosmetic ingredient (including as Pal-GHK)
4 notable studies · 5 references
TLDR
GHK is a naturally occurring human tripeptide (Gly-His-Lys) that binds copper tightly and is the parent peptide of GHK-Cu; cell and animal studies link it to tissue remodeling and gene-expression changes, but most evidence involves the copper complex, much comes from one research group, and there are no clinical trials of copper-free GHK.
At a Glance
Classification: Naturally occurring human tripeptide (Gly-His-Lys); high-affinity copper(II)-binding peptide; matrix-remodeling and gene-expression modulator studied mainly in cell and animal models
GHK is the tripeptide glycine-histidine-lysine. It was first found in human plasma in 1973 as a factor that helped liver cells survive in culture. GHK binds copper very tightly, and early work showed it forms complexes with copper and helps cells take it up. That is why GHK and GHK-Cu (the copper complex) are closely linked. Much of the published literature is about GHK-Cu, or does not clearly separate the free peptide from the copper complex. GHK is used in cosmetics, and a fatty-acid-attached form (palmitoyl tripeptide-1, Pal-GHK) is a common skin-care ingredient. GHK is not an approved drug.
What Is GHK (Copper-Free)?
GHK (copper-free) → Gly-His-Lys tripeptide alone GHK-Cu → GHK bound to copper(II); the form most studied for wound and skin effects Pal-GHK (palmitoyl tripeptide-1) → GHK with a palmitic acid attached to help skin penetration; used in cosmetic blends In body fluids, free GHK readily picks up copper, so "copper-free" GHK may not stay copper-free after it is applied or injected.
What Are Researchers Studying?
Copper transport
GHK co-purified with copper from plasma, readily formed copper(II) complexes and increased copper uptake into cultured liver-cancer cells. Several His-Lys tripeptides showed similar activity.
Tissue remodeling and lung disease
A gene-expression study of lung tissue from smokers with COPD identified GHK (via the Connectivity Map database) as a compound predicted to reverse the gene signature linked to emphysema. In cultured human lung fibroblasts, GHK switched on TGF-β-pathway genes, organized the actin cytoskeleton and increased integrin β1.
Skin and wound repair
Reviews by the original GHK research group describe GHK stimulating collagen, glycosaminoglycans and decorin and accelerating wound healing in animals, and cosmetic studies reporting improved skin firmness and fewer fine lines. Much of this work used GHK-Cu and comes largely from one research group.
Gene-expression modulation
Gene-database analyses suggest GHK can shift the expression of many genes toward patterns associated with tissue repair. These are computational and cell findings, not clinical outcomes.
How Does It Work?
Proposed mechanisms (largely preclinical): GHK ↓ binds copper(II) and may deliver it to cells and copper-dependent enzymes (such as lysyl oxidase and superoxide dismutase) ↓ changes in expression of genes for matrix remodeling, TGF-β signaling, integrins and antioxidant defense ↓ effects on collagen, glycosaminoglycans and fibroblast behavior in culture and animal wounds. No specific GHK receptor has been identified.
What Does the Research Show?
Human research
VERY LIMITED. Human data are mostly cosmetic studies of GHK-Cu or Pal-GHK products. No controlled clinical trials of copper-free GHK as a therapy were identified.
Animal research
MODERATE but concentrated: wound-healing studies in several species are described in reviews by the founding research group.
In-vitro research
MODERATE: cell-culture, copper-binding and gene-expression studies.
Notable Studies
Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver
in-vitroJournal: Nature New Biology. Original report of a tripeptide factor from human serum (later identified as GHK) that prolonged survival of normal liver cells and stimulated growth of liver-tumor cells in culture.
Limitations: Early cell-culture discovery study; record has no abstract.
View publication →Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells
in-vitroJournal: Nature. GHK co-isolated with copper, readily formed copper(II) complexes and enhanced copper uptake into cultured hepatoma cells. Effects ranged from growth stimulation to toxicity depending on the system.
Limitations: Cell-culture study; dates from 1980.
View publication →A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK
in-vitroJournal: Genome Medicine. In lung tissue from smokers with COPD, 127 genes tracked emphysema severity. Connectivity Map analysis identified GHK as reversing this signature; in human lung fibroblasts, GHK induced TGF-β-pathway gene expression, organized actin and increased integrin β1.
Limitations: Computational prediction plus cell experiments; no animal or human treatment data.
View publication →GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration
in-vitroJournal: BioMed Research International. Narrative review describing GHK effects on collagen, glycosaminoglycans, decorin, metalloproteinases, wound healing in several animal species, and cosmetic skin outcomes, largely proposed to act as a copper complex.
Limitations: Review written by the founding research group; mixes GHK and GHK-Cu data; much of the cited evidence is preclinical or cosmetic.
View publication →What We Still Don't Know
• Whether copper-free GHK has effects distinct from GHK-Cu, given that it binds copper readily in the body • Any controlled human clinical trial of copper-free GHK • Whether gene-signature reversal translates to lung, skin or other clinical benefit • Independent replication outside the founding research group • Long-term safety of repeated non-topical use
Related Compounds
Recent publications
Latest titles from PubMed, not reviewed by Aminodex. Not an endorsement. See all on PubMed ↗
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Sources & References
- Pickart L et al. Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver. Nature New Biology. 1973.
- Pickart L et al. Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells. Nature. 1980.
- Campbell JD et al. A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK. Genome Medicine. 2012.
- Pickart L et al. GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration. BioMed Research International. 2015.
- 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.
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