Ghk Cu: Mechanism of Action

Mechanism of Action

Copper Transport & "Redox Silencing"

GHK-Cu acts as a carrier peptide with high affinity for copper(II) ions (pKa = 16.44). The complex "silences" copper's redox activity, preventing Fenton reaction damage while delivering copper safely into cells — essential for enzymes like lysyl oxidase (collagen crosslinking) and superoxide dismutase (antioxidant defense).[3]

Key Signaling Pathways

Pathway	Mechanism	Effect
NF-κB/p38 MAPK	Inhibits phosphorylation of NF-κB p65 and p38 MAPK	Blocks nuclear translocation → suppresses TNF-α, IL-6 (Park et al., 2016)[4]
Nrf2/Keap1	Promotes Nrf2 dissociation from Keap1 → nuclear translocation	HO-1 transcription → antioxidant defense (Zhang et al., 2022)[5]
SIRT1/STAT3	Upregulates SIRT1 → deacetylates STAT3 → suppresses RORγt	Reduces Th17 inflammation; ↑ ZO-1/Occludin tight junctions (Mao et al., 2025)[6]
TGF-β	Context-dependent modulation	Restores in COPD lungs (Campbell et al., 2012); suppresses in scarring/fibrosis[7]

Ferritin Iron Blockade

GHK-Cu binds to ferritin channels → prevents Fe(II) release → reduces iron-catalyzed lipid peroxidation by 87% (Miller et al., 1990).[8]

Gene Modulation

GHK-Cu induces >50% change in expression of 31.2% of human genes. It resets gene expression to a "younger/healthier" state — suppressing inflammatory and metastatic genes while activating repair and remodeling genes. Analysis via the Broad Institute Connectivity Map confirmed GHK modulates >4,000 genes.[2][9]

ECM Synthesis

Stimulates Collagen I/III, elastin, GAGs, and decorin; modulates MMPs and TIMPs for balanced tissue remodeling.[10]

Anti-Cancer Activity

Reactivates apoptosis (caspases 3/7) in neuroblastoma, leukemia, and breast cancer cell lines. Reverses 70% of 54 metastasis genes in colon cancer via Connectivity Map analysis.[9]

Dose-Response: Biphasic

Collagen synthesis stimulation begins at 10⁻¹² M, peaks at 10⁻⁹ M (1 nanomolar), and disappears at higher concentrations. Systemic wound healing in animals at ~1.1 mg/kg — far below the toxic threshold (LD50 estimated ~23,000 mg in 70 kg human).[10][3]

GHK vs. GHK-Cu

Form	Key Difference
GHK (peptide alone)	Some efficacy (quenches lipid peroxidation by-products); copper complex required for most wound healing/gene effects
GHK-Cu	Full regenerative profile; "redox silences" copper for safe delivery; strong chelators abolish effects
HGK:Cu (analog)	SOD-mimetic activity 223-fold higher than native GHK-Cu