{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T12:24:19Z","timestamp":1787833459409,"version":"build-2784847793"},"reference-count":64,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, Timi\u0219oara, Romania"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Glycyl-L-histidyl-L-lysine (GHK) and its copper(II) complex GHK-Cu have been studied for matrix remodeling, inflammation, redox regulation, angiogenesis, and tissue repair, yet the literature frequently treats GHK-Cu as a single active ingredient despite formulation-dependent variation in coordination state, speciation, stability, pharmacokinetics, and toxicity. We critically evaluate GHK-Cu simultaneously as a bioactive metallopeptide and as a drug-delivery cargo, with explicit separation of apo-GHK, canonical GHK-Cu, GHK-derived copper peptides, and non-GHK copper-peptide systems. Methods: We conducted a structured systematic evidence-mapping review of PubMed\/MEDLINE, Europe PMC, major publisher platforms, ClinicalTrials.gov, backward citation chains, and official European Union, U.S., and ICH regulatory sources from database inception through 12 August 2026. Biological evidence level and chemical\/formulation quality were graded independently using an author-defined two-axis framework. Delivery studies were extracted against a fixed matrix comprising formulation, claimed loading, molar copper occupancy, labile copper, species-resolved release, factorial controls, stability\/manufacturability, and objective outcome. Quantitative pooling was not performed because active-entity definitions, formulations, doses, models, comparators, and endpoints were not quantitatively commensurable. Results: Preclinical data consistently support effects on matrix remodeling, epithelial repair, inflammatory\/redox regulation, and angiogenesis, but the clinical evidence remains sparse and does not meet contemporary active-entity quality standards. Historical cosmetic reports are small or incompletely characterized; a 13-participant post-CO2-laser study was negative on objective endpoints, whereas a 2026 18-participant split-face eyebrow study reported positive cosmetic hair outcomes but did not define GHK-Cu speciation or local exposure. The ongoing phase 2 acute-wound study NCT07437586 remains recruiting and has no efficacy results; its registration cannot be used as evidence of clinical translation. Across delivery studies, particle size, polydispersity, encapsulation efficiency, total peptide\/copper content, and bulk release are often reported, whereas molar occupancy, labile copper, and release of intact GHK-Cu versus apo-GHK\/free copper are usually not resolved. Conclusions: Translation is limited less by biological plausibility than by pharmaceutical definition and evidence attribution. We define the \u201cactive pharmaceutical entity\u201d operationally as the reproducible chemical state intended to mediate pharmacology at administration, not as an established regulatory designation or a claim that one immutable molecular species persists in biological fluids. We further propose, explicitly as an author-derived development framework rather than a consensus standard, a control strategy based on molar occupancy, route-specific labile copper specifications, orthogonal speciation, mechanism-linked potency, species-resolved release, factorial controls, route-specific safety decision thresholds, ICH-aligned stability, and GMP-scalable manufacture. Until these requirements are met and controlled clinical efficacy is demonstrated, GHK-Cu should be regarded as a promising but unproven therapeutic cargo rather than a clinically validated regenerative drug.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091077","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T12:03:43Z","timestamp":1787832223000},"page":"1077","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GHK-Cu as a Bioactive Metallopeptide and Drug-Delivery Cargo: Coordination Chemistry, Formulation Science, Therapeutic Evidence, and a Translational Roadmap"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4951-1702","authenticated-orcid":false,"given":"Diana-Maria","family":"Mateescu","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Clinical Hospital CF Timi\u0219oara, 1 G\u0103rii Street, 300166 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragos-Mihai","family":"Gavrilescu","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, Dental District, Z\u0103gazului 3, One Floreasca Vista, Sector 1, 014261 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruxandra-Ioana","family":"Mincioaga","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Colentina Clinical Hospital, 19-21 \u0218oseaua \u0218tefan cel Mare, 020125 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6025-5998","authenticated-orcid":false,"given":"Ana-Maria","family":"Pah","sequence":"additional","affiliation":[{"name":"Department of Cardiology, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy of Timi\u0219oara, Eftimie Murgu Square 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana-Olivia","family":"Toma","sequence":"additional","affiliation":[{"name":"Center for the Morphologic Study of the Skin (MORPHODERM), \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy of Timi\u0219oara, Eftimie Murgu Square 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8837-1558","authenticated-orcid":false,"given":"Daniela-Vasilica","family":"Serban","sequence":"additional","affiliation":[{"name":"Center for the Morphologic Study of the Skin (MORPHODERM), \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy of Timi\u0219oara, Eftimie Murgu Square 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7868-9266","authenticated-orcid":false,"given":"Cristiana Adina","family":"Avram","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy of Timi\u0219oara, Eftimie Murgu Square 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Laura","family":"Craciun","sequence":"additional","affiliation":[{"name":"Department of Cardiology, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy of Timi\u0219oara, Eftimie Murgu Square 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2806-9002","authenticated-orcid":false,"given":"Bogdan","family":"Enache","sequence":"additional","affiliation":[{"name":"Department of Cardiology, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy of Timi\u0219oara, Eftimie Murgu Square 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3896-9599","authenticated-orcid":false,"given":"Camelia-Oana","family":"Muresan","sequence":"additional","affiliation":[{"name":"Institute of Legal Medicine Timi\u0219oara, 1A Cire\u0219ului Street, 300610 Timi\u0219oara, Romania"},{"name":"Ethics and Human Identification Research Center, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy of Timi\u0219oara, Eftimie Murgu Square 2, 300041 Timi\u0219oara, Romania"},{"name":"Discipline of Forensic Medicine, Bioethics, Deontology, and Medical Law, Department of Neuroscience, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy of Timi\u0219oara, Eftimie Murgu Square 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","first-page":"85","article-title":"Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver","volume":"243","author":"Pickart","year":"1973","journal-title":"Nat. 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