What is GHK-CU (Glycine-Histidine-Lysine-Copper) and how is it used for wound healing?

GHK-Cu (Glycyl-Histidyl-Lysyl-Copper): A Naturally Occurring Tissue Remodeling Peptide

GHK-Cu is a naturally occurring tripeptide-copper complex that demonstrates significant wound healing and tissue regeneration properties through multiple mechanisms including collagen synthesis, anti-inflammatory effects, and gene modulation, though it lacks formal guideline recommendations for clinical use in wound management. 1, 2

Biochemical Structure and Natural Occurrence

• GHK is a tripeptide composed of glycine-histidine-lysine that naturally binds copper (Cu²⁺) with high affinity, forming the GHK-Cu complex 1, 3
• The peptide is found in human serum, saliva, and urine with levels averaging 200 ng/ml at age 20, declining to approximately 80 ng/ml by age 60 3
• GHK has copper affinity similar to the copper transport site on albumin 1
• Both copper-free GHK and GHK-Cu demonstrate biological activity, though some effects differ between the two forms 4

Mechanisms of Action in Wound Healing

Cellular Recruitment and Proliferation

• GHK-Cu attracts repair cells including macrophages, mast cells, and capillary endothelial cells to injury sites 1
• Increases proliferation of fibroblasts and keratinocytes 1, 4
• Enhances basal stem cell survival and stemness in skin through increased integrin expression (α6 and β1) 4
• Increases p63 and proliferating cell nuclear antigen (PCNA) positive cells in skin models 4

Anti-Inflammatory Properties

• Suppresses free radicals, thromboxane formation, and release of oxidizing iron 1
• Reduces transforming growth factor beta-1 (TGF-β1) and tumor necrosis factor alpha (TNF-α) 1
• Blocks protein glycation while increasing superoxide dismutase activity 1
• Promotes vessel vasodilation and blocks ultraviolet damage to keratinocytes 1

Extracellular Matrix Modulation

• Stimulates synthesis of collagen, elastin, and glycosaminoglycans (dermatan sulfate, chondroitin sulfate) 1, 2
• Increases matrix metalloproteinase-2 (MMP-2) expression and mRNA levels 5
• Simultaneously increases tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), providing balanced matrix remodeling 5
• The copper component is essential for MMP-2 stimulation, as GHK alone does not reproduce this effect 5
• Stimulates decorin, a small proteoglycan important for collagen organization 2

Growth Factor and Protein Synthesis

• Increases production of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF-2), and nerve growth factor (NGF) 1
• Enhances neurotrophins 3 and 4, and erythropoietin synthesis 1
• Promotes angiogenesis and nerve outgrowth 1

Gene Regulation

• GHK is capable of up- and downregulating at least 4,000 human genes, essentially resetting DNA to a healthier state 2
• Targets anti-inflammatory and epigenetic pathways 3

Clinical Applications and Evidence

Wound Healing

• GHK-Cu stimulates wound healing in numerous animal models (rats, mice, pigs) and humans 1, 2
• Accelerates healing of skin, hair follicles, gastrointestinal tract, boney tissue, and foot pads in animal studies 2
• Induces systemic wound healing effects beyond local application sites 2
• Restores replicative vitality to fibroblasts after radiation therapy 2

Skin Regeneration and Cosmetic Effects

• Controlled studies on aged skin demonstrate that GHK-Cu tightens skin, improves elasticity and firmness 1, 2
• Reduces fine lines, wrinkles, photodamage, and hyperpigmentation 1, 2
• Increases skin density and keratinocyte proliferation 2
• Improves hair transplant success and increases hair follicle size 1

Other Tissue Protection

• Protects hepatic tissue from tetrachloromethane poisoning 1
• Blocks stomach ulcer development and heals intestinal ulcers 1
• Promotes bone tissue healing 1
• Preliminary observations suggest potential for reversing cognitive impairment in aging mice 3

Important Clinical Context

Lack of Formal Guideline Support

• Major wound healing guidelines (IWGDF 2023, IDSA 2012) do not specifically address GHK-Cu as a recommended intervention 6
• Guidelines generally recommend against selecting agents that alter wound biology (including growth factors) in preference to accepted standards of care for diabetic foot ulcers 6
• The evidence base for topically applied biological agents in clinical wound care remains limited with concerns about methodological quality 6

Comparison to Other Growth Factors

• Unlike platelet-derived growth factor (PDGF) which has mixed evidence and is not strongly recommended by guidelines, GHK-Cu lacks large-scale randomized controlled trials 6
• Growth factor therapies generally have conditional or negative recommendations due to limited high-quality evidence 6

Practical Considerations

Forms and Delivery

• Both copper-free GHK and GHK-Cu demonstrate biological activity 4
• Copper-free GHK shows similar effects to GHK-Cu in increasing stemness and proliferative potential of epidermal basal cells 4
• However, copper is essential for certain effects like MMP-2 stimulation 5

Current Use

• GHK (with or without copper) is primarily used in cosmetic hair and skin care products rather than medical wound care 4
• The molecule has been proposed as a therapeutic agent for skin inflammation, chronic obstructive pulmonary disease, and metastatic colon cancer, though these applications require further investigation 2

Safety Profile

• The peptide demonstrates antioxidant and anti-inflammatory effects in vitro and in vivo studies 3
• No significant adverse effects are reported in the available literature 1, 3, 2

Key Limitations

• Despite promising preclinical data, GHK-Cu lacks the high-quality randomized controlled trials and guideline support necessary for routine clinical wound care recommendations 6
• Most evidence comes from in vitro studies, animal models, and cosmetic applications rather than controlled clinical trials in wound healing 1, 3, 2, 4, 5
• The rationale exists for further investigation in preclinical and clinical aging studies, but definitive clinical recommendations await stronger evidence 3