GHK-Cu (Copper Peptide) Research & Studies

The age-related decline in tissue regenerative capacity drives demand for interventions restoring physiological repair mechanisms. Glycyl-L-histidyl-L-lysine-copper (GHK-Cu) has demonstrated significant regenerative, anti-inflammatory, and antioxidant properties in preclinical models, prompting its increasing integration into aesthetic practice despite a paucity of standardized clinical guidelines. This systematic review evaluates the efficacy, safety, and regenerative mechanisms of GHK-Cu in aesthetic medicine to clarify its clinical utility and inform future research. A systematic search of PubMed, Embase, and Cochrane CENTRAL was conducted from database inception through March 2026, following PRISMA guidelines. Eligible studies included clinical and preclinical models investigating GHK-Cu as a standalone intervention for aesthetic applications. 20 studies (18 preclinical; 2 RCTs) were included. Preclinical data consistently demonstrated that GHK-Cu enhances extracellular matrix synthesis (type I collagen and glycosaminoglycans), modulates metalloproteinase activity, and promotes angiogenesis and cellular proliferation. It also exhibited significant anti-inflammatory effects by suppressing TGF-β and IL-6. Clinically, GHK-Cu improved patient-reported satisfaction after laser resurfacing and significantly reduced wrinkle volume and depth compared with controls. Additionally, advanced delivery systems, including microneedles and liposomes, markedly improved its transdermal bioavailability and efficacy. GHK-Cu demonstrates a reasonable biological basis for use as a regenerative agent in aesthetic medicine, supported by available preclinical data. Nevertheless, the findings reported across studies were constrained by methodological variability and a limited number of well-designed clinical trials. Future research incorporating larger, controlled trials with standardized formulations, dosing regimens, and delivery methods will be necessary to close the translational gap and inform the development of consistent therapeutic protocols in clinical practice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by mucosal damage and impaired epithelial barrier function. While glycyl-l-histidyl-l-lysine-copper (GHK-Cu) exhibits known anti-inflammatory properties, its therapeutic mechanisms in UC remain undefined. This study was designed to systematically evaluate the therapeutic potential of GHK-Cu in a dextran sulfate sodium (DSS)-induced murine model of UC, with particular emphasis on elucidating its regulatory effects on the NAD-dependent deacetylase sirtuin-1 (SIRT1)/signal transducer and activator of transcription 3 (STAT3) signaling pathway.

Cosmetically active compounds (CACs), both of lipophilic and hydrophilic origin, have difficulty reaching the deeper layers of the skin, and this shortcoming significantly reduces their efficacy. One such CAC that occurs naturally in the human body and displays many beneficial properties (via reducing fine lines and wrinkles, tightening skin, improving its elasticity, etc.) is the glycyl-L-histidyl-L-lysine tripeptide complex of copper (GHK-Cu). GHK-Cu is a fairly hydrophilic compound with limited permeation through the lipophilic stratum corneum. On the other hand, liposomes capable of encapsulating GHK-Cu may improve its permeation potential. The present review discusses various issues related to obtaining insight into the permeation of CACs through the skin. Methods for studying the transport of CACs encapsulated by liposomes and free GHK-Cu across the skin barrier are summarized. An analysis of the literature data reveals that the transport of liposomes containing GHK-Cu received little attention. This research gap gives an impetus to the methodological developments for assessing the effect of liposomes on GHK-Cu transportation and trafficking.

With the wide application of soft tissue fillers, implant material-induced inflammatory reactions have become a key factor affecting the therapeutic efficacy. This study developed an injectable filler with enhanced anti-inflammatory and antioxidant effects by adsorbing glycyl-L-histidyl-L-lysine copper complex (GHK-Cu) onto hydroxyapatite microspheres (HAPs), marking the first combination of HAPs and GHK-Cu to address inflammation caused by soft tissue fillers. GHK-Cu was successfully loaded onto HAPs by electrostatic adsorption. HAPs were then mixed with carboxymethyl cellulose (CMC), glycerol (GLY), and water to form GHK-Cu@CMHA gel. The study focus on the effective combination of HAPs as a carrier for sustained GHK-Cu delivery and the anti-inflammatory properties of GHK-Cu. GHK-Cu@CMHA exhibits sustained release properties for 7 days, which ensures prolonged therapeutic effects, minimizes peptide waste and reduces injection frequency, with good flowability and injectability. In the model of LPS-induced inflammation model in vivo and in vitro, GHK-Cu@CMHA gel reduced levels of inflammatory factors and Reactive oxygen species (ROS) levels decreased, while superoxide dismutase (SOD) activity was enhanced. In this process, H&E staining and Masson staining revealed significant collagen deposition. These findings further confirm that GHK-Cu@CMHA is a novel injectable soft tissue filler with good anti-inflammatory and antioxidant properties, which holds well potential for inflammation inhibition.

The hyphenation of the separation technique with the high-sensitive mass spectrometry detection is one of the driving forces of modern analysis enabling measurements in complex matrices. In particular, capillary electrophoresis coupled to inductively coupled plasma tandem mass spectrometry allows for speciation analysis of selected analytes with a superior resolution. The mild, physiological-friendly conditions of this separation technique offer the unique advantage of analyzing chemical entities in their intact form, which has been successfully exploited in various areas. Herein, we report the pioneering application of such a hyphenated technique in the cosmetic field to investigate the encapsulation of copper tripeptide complex (GHK-Cu) in liposomes. By monitoring copper and phosphorus signals, the formation of liposomes via a simple ethanol injection method was confirmed, and the concentration of GHK-Cu in the liposomes was assessed. The application of coupling of capillary electrophoresis with inductively coupled plasma tandem mass spectrometry (CE-ICP-MS/MS) in cosmetic studies could lead to the development of diverse liposomal formulations with preferential properties and expand their accessibility.

Sensing important metals in different environments is an important area and involves the development of a wide variety of metal-sensing materials. The employment of fluorescent sensors in metal sensing has been one of the most widely applied methodologies, and the identification of selective metal sensors is important. We herein report a phenothiazine-based Cu(II) fluorescent sensor that is highly selective to Cu(II) ions compared with other transition metal salts. The Lewis acidity of the Cu(II) salt certainly was found to be a factor for obtaining an enhanced sensing response in MeOH as the solvent, while a ratio of 1:1 was calculated to be the most optimum for getting the desired response.

Bioactive glasses and peptides have shown promising results in improving wound healing and skin repair. The present study explores the effectiveness of surface modification of collagen/chitosan-coated electrospun poly(ε-caprolactone) scaffold with 58S bioactive glass or GHK-Cu peptide. To coat scaffolds with the bioactive glass, we prepared suspensions of silanized bioactive glass powder with three different concentrations and the scaffolds were pipetted with suspensions. Similarly, GHK-Cu-coated scaffolds were prepared by pipetting adequate amount of 1-mM solution of peptide (in milli-Q) on the surface of scaffolds. ATR-FTIR spectroscopy indicated the successful modification of collagen/chitosan-coated electrospun poly(ε-caprolactone) scaffold with bioactive glass and GHK-Cu. Microstructural investigations and in vitro studies such as cell adhesion, cell viability and antibacterial assay were performed. All samples demonstrated desirable cell attachment. Compared to poly(ε-caprolactone)/collagen/chitosan, the cell proliferation of GHK-Cu and bioactive glass-coated (concentrations of 0.01 and 0.1) scaffolds increased significantly at days 3 and 7, respectively. Poly(ε-caprolactone)/collagen/chitosan-uncoated scaffold and scaffolds coated with GHK-Cu and bioactive glass revealed desirable antibacterial properties but the antibacterial activity of GHK-Cu-coated sample turned out to be superior. These findings indicated that biological properties of collagen/chitosan-coated synthetic polymer could be improved by GHK-Cu and bioactive glass.

Idiopathic pulmonary fibrosis (IPF) is a serious lung problem with advancing and diffusive pulmonary fibrosis as the pathologic basis, and with oxidative stress and inflammation as the key pathogenesis. Glycyl-L-histidyl-l-lysine (GHK) is a tripeptide participating into wound healing and regeneration. GHK-Cu complexes improve GHK bioavailability. Thus, the current study aimed to explore the therapeutic role of GHK-Cu on bleomycin (BLM)-induced pulmonary fibrosis in a mouse model.

Hepcidin-25 was identified as the main iron regulator in the human body, and it by binds to the sole iron-exporter ferroportin. Studies showed that the N-terminus of hepcidin is responsible for this interaction, the same N-terminus that encompasses a small copper(II)-binding site known as the ATCUN (amino-terminal Cu(II)- and Ni(II)-binding) motif. Interestingly, this copper-binding property is largely ignored in most papers dealing with hepcidin-25. In this context, detailed investigations of the complex formed between hepcidin-25 and copper could reveal insight into its biological role. The present work focuses on metal-bound hepcidin-25 that can be considered the biologically active form. The first part is devoted to the reversed-phase chromatographic separation of copper-bound and copper-free hepcidin-25 achieved by applying basic mobile phases containing 0.1% ammonia. Further, mass spectrometry (tandem mass spectrometry (MS/MS), high-resolution mass spectrometry (HRMS)) and nuclear magnetic resonance (NMR) spectroscopy were employed to characterize the copper-peptide. Lastly, a three-dimensional (3D) model of hepcidin-25 with bound copper(II) is presented. The identification of metal complexes and potential isoforms and isomers, from which the latter usually are left undetected by mass spectrometry, led to the conclusion that complementary analytical methods are needed to characterize a peptide calibrant or reference material comprehensively. Quantitative nuclear magnetic resonance (qNMR), inductively-coupled plasma mass spectrometry (ICP-MS), ion-mobility spectrometry (IMS) and chiral amino acid analysis (AAA) should be considered among others.

The human peptide GHK (glycyl-l-histidyl-l-lysine) has multiple biological actions, all of which, according to our current knowledge, appear to be health positive. It stimulates blood vessel and nerve outgrowth, increases collagen, elastin, and glycosaminoglycan synthesis, as well as supports the function of dermal fibroblasts. GHK’s ability to improve tissue repair has been demonstrated for skin, lung connective tissue, boney tissue, liver, and stomach lining. GHK has also been found to possess powerful cell protective actions, such as multiple anti-cancer activities and anti-inflammatory actions, lung protection and restoration of chronic obstructive pulmonary disease (COPD) fibroblasts, suppression of molecules thought to accelerate the diseases of aging such as NFκB, anti-anxiety, anti-pain and anti-aggression activities, DNA repair, and activation of cell cleansing via the proteasome system. Recent genetic data may explain such diverse protective and healing actions of one molecule, revealing multiple biochemical pathways regulated by GHK.

Glycyl-l-histidyl-l-lysine (GHK)-Cu is considered to be an activator of tissue remodeling, and has been used in cosmetic products. In this study, we prepared liposomes encapsulating GHK-Cu and analyzed their effect on human umbilical vein endothelial cells (HUVECs) proliferation and scald wound healing in mice. The nanoscaled GHK-Cu-liposomes promoted HUVECs proliferation, with a 33.1% increased rate. Flow cytometry analysis showed increased cell number at G1 stage and decreased cell number at G2 stage after GHK-Cu-liposomes treatment. Western blotting indicated that the expression of vascular endothelial growth factor and fibroblast grow factors-2 were both enhanced, as well as cell cycle-related proteins CDK4 and CyclinD1. In a mice scald model, angiogenesis in burned skin treated with GHK-Cu-liposomes was better compared with free GHK-Cu, and immunofluorescence analysis showed enhanced signal of CD31 and Ki67 in GHK-Cu-liposomes treated mice. Moreover, the wound healing time was shortened to 14 days post injury. Our results provide the evidence that GHK-Cu-liposomes could be utilized as a treatment for skin wounds.

The tripeptide-copper complex glycyl-l-histidyl-l-lysine-Cu (II) (GHK-Cu) is involved in wound healing and tissue remodeling. Although GHK-Cu exhibits anti-aging and tissue renewing properties, its roles in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are still unknown. Therefore, we examined the effects of GHK-Cu in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages in vitro and ALI in mice in vivo. GHK-Cu treatment reduced reactive oxygen species (ROS) production, increased superoxide dismutase (SOD) activity while decreased TNF-α and IL-6 production through the suppression of NF-κB p65 and p38 MAPK signaling in vitro and in vivo model of ALI. Moreover, GHK-Cu attenuated LPS-induced lung histological alterations, suppressed the infiltration of inflammatory cells into the lung parenchyma in LPS-induced ALI in mice. Taken together, these findings demonstrate that GHK-Cu possesses a protective effect in LPS-induced ALI by inhibiting excessive inflammatory responses; accordingly it may represent a novel therapeutic approach for ALI/ARDS.

Copper peptide (GHK-Cu) plays an important role in skin regeneration and wound healing. However, its skin absorption remains challenging due to its hydrophilicity. Here we use polymeric microneedle array to pre-treat skin to enhance GHK-Cu skin penetration.

After anterior cruciate ligament reconstruction (ACLR), the biological healing of the graft is a rate-limiting step which can contribute to graft failure. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(II) (GHK-Cu) is a well-known activator of tissue remodeling. We investigated whether GHK-Cu can improve graft healing following ACLR. Seventy-two rats underwent unilateral ACLR were randomized to saline, 0.3 or 3 mg/ml GHK-Cu groups (n = 24). Post-operational intra-articular injections were given from week 2, once a week, for 4 weeks. Gait analysis was performed pre-injury and at harvesting time. At 6 or 12 weeks post-operation, knee specimens were harvested for knee laxity test, graft pull-out test, and histology. At 6 weeks post-ACLR, GHK-Cu groups resulted in a smaller side-to-side difference in knee laxity as compared to the saline group (p = 0.009), but there was no significant difference at 12 weeks post-operation. The graft complex in the 0.3 mg/ml GHK-Cu group had higher stiffness than saline group at 6 weeks post-operation (p = 0.026), but there was no significant difference in ultimate load, gait parameters, and histological scores among treatment groups. All grafts failed mid-substance during pull-out test. Intra-articular supplementation with a bioactive small molecule GHK-Cu improved graft healing following ACLR in rat, but the beneficial effects could not last as treatment discontinued.

Oxidative stress, disrupted copper homeostasis, and neuroinflammation due to overproduction of proinflammatory cytokines are considered leading causative factors in development of age-associated neurodegenerative conditions. Recently, a new mechanism of aging-detrimental epigenetic modifications-has emerged. Thus, compounds that possess antioxidant, anti-inflammatory activity as well as compounds capable of restoring copper balance and proper gene functioning may be able to prevent age-associated cognitive decline and ward off many common neurodegenerative conditions. The aim of this paper is to bring attention to a compound with a long history of safe use in wound healing and antiaging skin care. The human tripeptide GHK was discovered in 1973 as an activity in human albumin that caused old human liver tissue to synthesize proteins like younger tissue. It has high affinity for copper ions and easily forms a copper complex or GHK-Cu. In addition, GHK possesses a plethora of other regenerative and protective actions including antioxidant, anti-inflammatory, and wound healing properties. Recent studies revealed its ability to up- and downregulate a large number of human genes including those that are critical for neuronal development and maintenance. We propose GHK tripeptide as a possible therapeutic agent against age-associated neurodegeneration and cognitive decline.