Overview
Palmitoyl Pentapeptide-4, also known by its CAS number 214047-00-4 and sometimes referred to as Palmitoyl Pentapeptide-3, is a synthetic lipopeptide composed of a five-amino-acid chain — lysine, threonine, threonine, lysine, and serine — attached to a palmitoyl (fatty acid) group that helps facilitate its penetration through lipid barriers in laboratory settings. It belongs to a class of compounds known as signal peptides or matrikines, which are short peptide sequences that have been studied for their ability to interact with extracellular matrix processes in cell-based research models. The palmitoyl modification distinguishes it from its unmodified peptide counterpart and is a common structural feature studied in research exploring how lipid conjugation affects peptide behavior and delivery. With a molecular weight of approximately 802.1 Da and the molecular formula C39H75N7O10, it has been the subject of published in vitro research examining topics such as transdermal delivery mechanisms, fibroblast interactions, and extracellular matrix gene expression. Palmitoyl Pentapeptide-4 is intended strictly for laboratory and research use only and is not approved or intended for human consumption or therapeutic application.
Research & Bioactivity
Palmitoyl Pentapeptide-4 is a synthetic signal peptide that researchers have studied primarily in the context of skin biology, with particular interest in its relationship to extracellular matrix components such as collagen and elastin. In vitro studies have examined its potential interactions with dermal fibroblasts, including investigations into how it may influence gene expression related to extracellular matrix synthesis when combined with other bioactive agents. Researchers have also investigated its behavior in the context of transdermal delivery systems, exploring how formulation approaches such as nanomicelles and dendrimers affect the peptide's ability to penetrate the skin's outer layers and reach the deeper living tissue. Clinical research has included double-blind, randomized trials examining topical applications in human subjects, with studies exploring outcomes related to visible signs of skin aging in diverse populations, including comparative work conducted in Asian skin types. Additionally, safety evaluation frameworks developed for cosmetic peptides have been applied to compounds in this class, reflecting ongoing scientific interest in characterizing the risk profile of signal peptides used in topical research and cosmetic formulations.
Published Research
A framework for the safety evaluation of peptides in cosmetics.
Bjerke DL, Li J, Gao Y, Hu P, Lintner K, et al. — 2026
As the cosmetic industry replaces traditional animal safety studies with next generation risk assessment approaches, the approach to safety substantiation for peptides used in cosmetic products must also evolve. While the need to provide assurances of safety for local and systemic toxicity endpoints remains the same, adoption of bioinformatic tools developed in the food, agricultural biotechnology, and drug development industries may add to the weight of evidence for the safety substantiation of peptides in cosmetics. Here we review the historical development and safety evaluation of peptides utilized in the cosmetic industry and provide a new safety evaluation framework that incorporates six bioinformatic tools. To test the framework, a variety of peptides (palmitoyl hexapeptide-12, caffeoyl hexapeptide-9, palmitoyl pentapeptide-4, amanitin alpha, conotoxin ArlB, bradykinin, and enkephaline) are evaluated with NCBI BLASTp, ToxinPred3.0, Peptipedia, BIOPEP-UWM, AllerCatPro 2.0, and IEDB bioinformatic tools. The results correctly identified safety concerns (toxins) for amanitin and conotoxin peptides and the biological actions of bradykinin and enkephaline, while palmitoyl hexapeptide-12, caffeoyl hexapeptide-9, and palmitoyl pentapeptide-4 demonstrated sequence homology with extracellular matrix proteins in the skin (collagen, elastin, fibronectin) without the safety concerns of the other peptides. The incorporation of bioinformatic tools into the safety framework provides an additional means to screen for toxins and allergens as well as insights into potential biological activities when sequence homology with existing proteins and peptides occurs. Further testing of the framework by the cosmetic industry is needed to lend support and reveal opportunities for refinements that advance the safety substantiation of peptides.
Synergistic Effects of Injectable Platelet-Rich Fibrin and Bioactive Peptides on Dermal Fibroblast Viability and Extracellular Matrix Gene Expression: An In Vitro Study.
Paccola AGL, Santos TMCD, Minelo MC, Garbieri TF, Sanches MLR, et al. — 2025
Facial aging is a multifactorial process involving changes in bone, fat compartments, ligaments, muscles, and skin. Collagen biostimulators, including synthetic agents and autologous platelet concentrates, have gained attention for facial rejuvenation. Injectable platelet-rich fibrin (i-PRF), a second-generation autologous concentrate, has shown promising regenerative properties due to its natural composition and growth factors. Cosmetic peptides, such as palmitoyl pentapeptide-4 (Matrixyl) and Tetrapeptide-21 (GEKG), are also studied for their ability to stimulate collagen synthesis and remodel the extracellular matrix. This in vitro study examined the potential synergistic effects of i-PRF combined with Matrixyl or GEKG on human dermal fibroblast viability, proliferation, and ECM-related gene expression. Fibroblasts were cultured under six conditions: control, i-PRF alone, Matrixyl alone, GEKG alone, i-PRF + Matrixyl, and i-PRF + GEKG. Viability and proliferation were assessed via MTT, crystal violet, and RealTime-Glo™ assays. Gene expression of , , and was measured using RT-qPCR. The combinations, especially i-PRF + GEKG, led to increased cell viability and upregulated ECM-related genes at 72 h. These effects were stronger than the individual treatments, suggesting synergistic effects, especially with GEKG. These findings highlight the clinical potential of combining autologous platelet concentrates with bioactive peptides for dermal regeneration. Further preclinical and clinical studies are warranted.
Bioactive Glycyrrhizic Acid Ionic Liquid Self-Assembled Nanomicelles for Enhanced Transdermal Delivery of Anti-Photoaging Signal Peptides.
Wang Z, Liu J, Chen Q, Wu Y, Li Y, et al. — 2025
Sigal peptides have garnered remarkable efficacy in rejuvenating photoaged skin and delaying senescence. Nevertheless, their low solubility and poor permeability bring about a formidable challenge in their transdermal delivery. To address this challenge, bioactive ionic liquids (ILs) synthesized from natural glycyrrhizic acid (GA) and oxymatrine (OMT) with eminent biocompatibility is first prepared. The components ratios and inherent forming mechanisms of GA-OMT (GAO) are optimized by molecular dynamics simulations and density functional theory calculations. Remarkably, GAO can significantly improve the sparingly soluble properties of palmitoyl pentapeptide-4 (PAL-4), a model peptide drug. Subsequently, GAO self-assembled micelles loading PAL-4 (GAO/PAL-4-SM) are fabricated without additional auxiliary materials. The permeation and subcutaneous retention of PAL-4 are significantly promoted with 10wt.% GAO-SM. Moreover, GAO ILs facilitated PAL-4 permeation by enhancing its miscibility and interaction with stratum corneum (SC), offering a pulling effect and micellar structures for PAL-4, as elucidated by computational simulations. In cellular and animal photoaging experiments, GAO/PAL-4-SM possessed remarkable capabilities in boosting collagen and hyaluronic acid regeneration, mitigating inflammation and apoptosis, accelerating macrophage M2 polarization, thereby lessening skin wrinkles and leveraging elasticity. Collectively, the research innovatively designed an ILs self-assembled nano-micellar transdermal delivery system to enhance the permeability and anti-photoaging effect of signal peptides.
Dually functionalized dendrimer for stimuli-responsive release of active ingredients into the skin.
Trashi O, Satish N, Trashi I, Hagge LM, Wijesundara YH, et al. — 2025
The skin, our largest organ, protects against environmental dangers but is vulnerable to various conditions like infections, eczema, dermatitis, psoriasis, skin cancer, and age-related collagen and elastin degradation. Its outer layer, the water-impermeable epidermis, presents challenges for passive drug delivery to the lower living layers of the skin. An ideal dermal delivery system should penetrate the epidermis and release treatments over time. We report a stimuli-activated nanocarrier that slowly releases active ingredients under skin-specific conditions. Using a fourth-generation polyamidoamine (PAMAM), dendrimer functionalized with poly(2-ethyl-2-oxazoline) and palmitoyl pentapeptide-4, we show a controlled release of biologically active therapeutics into the dermis of the skin for 24 h. Ex vivo studies demonstrate that our nanocarrier system delivers cargo to the dermis and is non-toxic to skin fibroblasts. As a proof of principle, we demonstrate a system that effectively enhances collagen production in human dermal fibroblasts by co-delivering all-trans retinol and palmitoyl pentapeptide-4. Our nanosystem surpasses the effects of individual components. This nanocarrier offers a promising approach for targeted dermal delivery, potentially improving treatment efficacy for various skin conditions while minimizing adverse effects associated with traditional formulations. STATEMENT OF SIGNIFICANCE: In this manuscript we introduce a stimuli-responsive nanocarrier based on a G4-PAMAM dendrimer functionalized with poly(2-ethyl-2-oxazoline) (POZ) and palmitoyl pentapeptide-4, designed to deliver biomolecules specifically to the skin. The nanocarrier enables controlled, stimuli-triggered release under skin-specific conditions (pH 5, 37 °C), enhancing dermal penetration and minimizing release at neutral pH or lower temperatures. This work improves traditional dendrimer systems by reducing toxicity through POZ, ensuring controlled delivery without invasive techniques like iontophoresis, and co-delivering both a small molecule (all-trans-retinol) and a collagen-stimulating peptide for enhanced therapeutic effects. This system addresses major drug delivery challenges, sets a new precedent for safer, multifunctional nanomaterials, and advances dendrimer chemistry, opening new possibilities in targeted therapies, skin treatments, and materials science.
Double-blind, Randomized Trial on the Effectiveness of Acetylhexapeptide-3 Cream and Palmitoyl Pentapeptide-4 Cream for Crow's Feet.
Aruan RR, Hutabarat H, Widodo AA, Firdiyono MTCC, Wirawanty C, et al. — 2023
BACKGROUND: Crow's feet is one of the signs of skin aging. Many studies regarding skin aging have been carried out in Caucasians, as for Asians, there are different genotypes and phenotypes. Some anti-aging treatments carry a slightly higher risk of side effects and irritation in Asian skin. Currently, the use of topical active peptides for anti-aging, Acetylhexapeptide-3 (AHP-3) and Palmitoyl pentapeptide-4 (PPP-4), has been widely developed. This study aimed to investigate the anti-aging effects of AHP-3 and PPP-4 on the Asian patient with crow's feet. METHODS: This study was a double-blind randomized trial using 21 Indonesian female subjects aged 26 to 55 years for eight weeks and divided into three groups: AHP-3 cream, PPP-4 cream, and placebo. The cream was applied twice daily to the periorbital area. The three groups were assessed using Corneometer, Tewameter, Cutometer, digital photography and Crow's Feet Grading Scale. RESULTS: Based on clinical photos and data, improvements were found in several subjects using AHP-3 and PPP-4. PPP-4 appeared to demonstrate better results when compared to AHP-3 based on data, clinical photos, and self-assessment questionnaire. CONCLUSION: PPP-4 demonstrated better results when compared to AHP-3 and placebo. This initial study provides an opportunity for further study with a more adequate number of samples and duration.