Synergy of GHK-Cu and hyaluronic acid on collagen IV upregulation via fibroblast and ex-vivo skin tests

J Cosmet Dermatol. 2023 Sep;22(9):2598-2604. doi: 10.1111/jocd.15763. Epub 2023 Apr 16.


Introduction: GHK-Cu and HA are two commonly used skin care ingredients, both of which were reported to enhance collagen synthesis. This work aims to investigate their co-effect on collagen regulation.

Materials and methods: In cell experiments, human dermal fibroblasts were treated by a series of GHK-Cu and HA combinations, and the expressions of collagen I, IV, and VII were measured by qRT-PCR. The best formula screened out from cell experiments were further studied by ex-vivo skin model, and the content of collagen IV was quantified by immunofluorescence method.

Results: The combination GHK-Cu and HA was found to promote the generation of collagen I, IV, and VII. Especially, they form a synergy on collagen IV. At the ratio of 1:9, GHK-Cu and LMW HA deliver the strongest effect to elevate collagen IV synthesis by 25.4 times in cell test and 2.03 times in ex-vivo skin test.

Conclusion: The co-effect of GHK-Cu and HA was revealed. Their synergy brings an insight to anti-aging technology: choosing proper molecular weight of HA and managing its ratio with GHK-Cu could enhance DEJ health via stimulating collagen IV synthesis.

Keywords: collagen; hyaluronic acid; skin care; synergy.

MeSH terms

  • Collagen Type I* / metabolism
  • Collagen Type IV / metabolism
  • Fibroblasts
  • Humans
  • Hyaluronic Acid* / metabolism
  • Hyaluronic Acid* / pharmacology
  • Skin Tests
  • Up-Regulation


  • glycyl-histidyl-lysine
  • Hyaluronic Acid
  • Collagen Type I
  • Collagen Type IV