# Palmitoyl Pentapeptide-4

> Palmitoyl pentapeptide-4 is a synthetic lipopeptide consisting of the five-residue sequence lysine-threonine-threonine-lysine-serine (KTTKS), a fragment of type I procollagen, with a palmitoyl chain on its N-terminus. Also called Pal-KTTKS, it is a cosmetic ingredient studied in fibroblast, animal and skin-permeation models and in a placebo-controlled facial skin trial. It is not an FDA-approved drug.

Canonical: https://peptideproperties.com/compounds/palmitoyl-pentapeptide-4/

## Identity

- **Class:** Copper & Cosmetic Peptides
- **Also known as:** Pal-KTTKS, Palmitoyl pentapeptide-3
- **Molecular formula:** C39H75N7O10
- **Molecular weight:** 802.1 g/mol
- **Monoisotopic mass:** 801.5575 Da
- **CAS number:** 214047-00-4
- **PubChem CID:** 9897237
- **InChIKey:** WSGCRSMLXFHGRM-DEVHWETNSA-N
- **Sequence notes:** Lys-Thr-Thr-Lys-Ser (KTTKS) with an N-terminal palmitoyl (hexadecanoyl) amide on the first lysine; free C-terminal carboxylic acid on serine.

## Key facts

- Class: lipidated (palmitoylated) pentapeptide; matrikine-derived cosmetic peptide
- Sequence core: KTTKS, residues 212–216 of type I procollagen
- Modification: N-terminal palmitoyl group; free C-terminal carboxylic acid on serine
- Formula C39H75N7O10; molecular weight 802.1 g/mol (PubChem CID 9897237)
- CAS 214047-00-4; former name palmitoyl pentapeptide-3
- Evidence base: in-vitro, animal and permeation studies plus one 12-week split-face trial
- Regulatory status: cosmetic ingredient; not approved by the FDA as a drug

## What Is Palmitoyl Pentapeptide-4?

Palmitoyl pentapeptide-4 is the palmitoylated form of KTTKS (Lys-Thr-Thr-Lys-Ser), a synthetic peptide designed as a topical agent to stimulate collagen production in skin. It is widely abbreviated Pal-KTTKS.[1]The KTTKS sequence corresponds to residues 212 to 216 of type I procollagen.[2] It is classed as a matrikine, a peptide released by proteolytic breakdown of extracellular matrix proteins, and in vitro it has been reported to stimulate extracellular matrix production and the expression of type I and type III collagen. Pal-KTTKS was developed as a more stable form of the parent pentapeptide.[3]Compared head to head in hairless mouse skin, Pal-KTTKS was more stable and penetrated skin layers better than unmodified KTTKS.[4] It is one of the most studied cosmetic peptides, with research spanning analytical chemistry, delivery systems, fibroblast biology, wound models and a controlled facial skin trial.

## Chemical Structure and Molecular Identity

Palmitoyl pentapeptide-4 is N-palmitoyl-L-lysyl-L-threonyl-L-threonyl-L-lysyl-L-serine, a five-residue peptide with a 16-carbon fatty acid chain attached to the first lysine. PubChem (CID 9897237) lists the molecular formula C39H75N7O10 and a molecular weight of 802.1 g/mol. The CAS number is 214047-00-4.The peptide portion contains two lysine residues, which carry positively charged side-chain amines, and three hydroxyl-bearing residues (two threonines and a serine). The C-terminal serine has a free carboxylic acid. Attaching the palmitoyl chain makes the molecule amphiphilic: in one formulation study, N-palmitoyl-KTTKS integrated into the bilayer of phosphatidylcholine vesicles rather than staying in the aqueous phase.[5]Pal-KTTKS can be quantified in skin samples by liquid chromatography with tandem mass spectrometry (LC-MS/MS), a method developed specifically for its stability and permeation testing.[4]
### Names and synonyms

- INCI name: palmitoyl pentapeptide-4
- Former name: palmitoyl pentapeptide-3
- Abbreviations: Pal-KTTKS, Pal-Lys-Thr-Thr-Lys-Ser-OH

## Research History and Development

Pal-KTTKS was designed as a collagen-stimulating topical ingredient, and its first published controlled human study appeared in 2005. That double-blind, placebo-controlled, split-face trial in 93 women aged 35 to 55 compared a moisturizer with and without Pal-KTTKS over 12 weeks.[1]In the following decade, gene expression profiling of aged skin combined with in-vitro skin cell cultures was used to screen cosmetic compounds, and a 2012 review listed Pal-KTTKS among the ingredients whose biological effects were characterized this way, alongside niacinamide and retinyl propionate.[6] Related work tested Pal-KTTKS in multi-ingredient complexes on adult human fibroblasts.[7]Pal-KTTKS has also become a reference compound in its own right. It served as the reference peptide when researchers developed an LC-MS/MS assay for the stability of cosmetic peptides in skin homogenates.[8] More recent studies have focused on delivery systems, including liposomes, ionic-liquid micelles and wound dressings, to address its limited solubility and permeability.[5][9][10]

## Mechanisms Studied in Research

The main mechanism studied for Pal-KTTKS is stimulation of collagen and extracellular matrix production by fibroblasts; researchers have also examined effects on protease activity and on myofibroblast differentiation.
### Extracellular matrix production
The KTTKS sequence stimulates extracellular matrix production and type I and III collagen expression in vitro.[3] In NIH-3T3 fibroblasts, Pal-KTTKS delivered in phosphatidylcholine liposomes stimulated collagen production more than free pentapeptide and more than ascorbic acid used as a positive control.[5]
### Protease inhibition
In a series of KTTKS analogues carrying acetyl, lipoyl or palmitoyl groups, the palmitoyl peptides, in both acid and amide forms, were the most active inhibitors of the protease plasmin among the enzymes tested. None of the analogues was cytotoxic to fibroblasts, replacing lysine with arginine had no detectable effect, and the three analogues that promoted fibroblast growth showed no concentration-activity relationship in collagen and DNA biosynthesis assays.[3]
### Myofibroblast differentiation
Pal-KTTKS has been studied for its effect on fibroblast contractility in the context of hypertrophic scarring. In collagen lattice and cell culture experiments, it reduced expression of α-smooth muscle actin (α-SMA) and the transformation of fibroblasts into myofibroblasts, and the authors also measured connective tissue growth factor (CTGF).[2]
### Gene expression
In adult human fibroblasts, a complex containing niacinamide, Pal-KTTKS and an olive oil fatty acid derivative increased procollagen-1 and NAD+/NADH levels and the expression of matrix genes such as COL1A1, COL3A1 and ELN, while MMP1 expression decreased. Because the complex combined several actives, the effects cannot be assigned to Pal-KTTKS alone.[7]

## Key Findings From Published Studies

Pal-KTTKS has one placebo-controlled human trial, several fibroblast studies and a small number of animal studies, mostly involving delivery systems. Key results by model:
### Human trial

- In a 12-week, double-blind, split-face trial in 93 women with photoaged facial skin, Pal-KTTKS was well tolerated and significantly reduced wrinkles and fine lines versus placebo by quantitative image analysis and expert grading; participants also reported improvements in self-assessment.[1]
### In vitro

- In collagen lattices, about three quarters of untreated fibroblasts differentiated into myofibroblasts; the lower tested concentration of Pal-KTTKS roughly halved the proportion of α-SMA-positive stress fibers, while the higher concentration had no significant effect.[2]
- Liposome-encapsulated Pal-KTTKS increased fibroblast collagen production more than the free peptide.[5]
### Skin stability and permeation

- Both KTTKS and Pal-KTTKS were rapidly degraded in hairless mouse skin extracts, but Pal-KTTKS was more stable, and protease inhibitors improved the stability of both.[4]
- Neither peptide crossed full-thickness mouse skin into the receptor solution, but Pal-KTTKS was found in the stratum corneum, epidermis and dermis, with levels decreasing with depth; unmodified KTTKS was not detected in any layer.[4]
- In an LC-MS/MS stability assay optimized in rat skin homogenates with Pal-KTTKS as the reference substrate, its degradation profile was then characterized in human skin samples and compared with the rat results.[8]
### Animal studies

- In a rat burn wound model, carboxylated cellulose dressings enriched with Pal-KTTKS improved wound closure, collagen deposition and angiogenesis compared with control dressings; adding adipose-derived mesenchymal stem cells gave the best results.[9]
- Glycyrrhizic acid ionic-liquid micelles increased skin permeation and retention of Pal-KTTKS, and in cell and animal photoaging models the loaded micelles increased collagen and hyaluronic acid regeneration and reduced inflammation and wrinkles.[10]Because stability and palmitoylation drive Pal-KTTKS behavior in these studies, researchers typically confirm identity and purity with HPLC and mass spectrometry certificates of analysis.Because stability and palmitoylation drive Pal-KTTKS behavior in these studies, researchers typically confirm identity and purity with HPLC and mass spectrometry certificates of analysis.

## Regulatory and Research Status

Palmitoyl pentapeptide-4 is a cosmetic ingredient and is not approved by the US Food and Drug Administration as a drug for any indication. Cosmetic ingredients in the United States do not require FDA premarket approval, and cosmetic use does not establish safety or efficacy for other purposes.As a research compound, Pal-KTTKS is used to study fibroblast collagen synthesis, peptide stability against skin proteases, and topical delivery. Its human evidence remains limited to cosmetic endpoints, chiefly the 2005 split-face trial on facial wrinkles.[1] The authors of the scarring study cautioned that the balance between its wound-healing and pro-fibrotic activities needs to be considered in any therapeutic application.[2]Open questions include how much intact peptide reaches the dermis from conventional formulations, given its rapid degradation in skin homogenates, and whether delivery systems that perform well in animal models translate to human skin.[4][10]

## FAQ

**Is palmitoyl pentapeptide-4 the same as palmitoyl pentapeptide-3?**
Yes. Palmitoyl pentapeptide-3 is an earlier name for the same molecule, N-palmitoyl-Lys-Thr-Thr-Lys-Ser (Pal-KTTKS), and PubChem lists both names for CID 9897237. The current INCI name is palmitoyl pentapeptide-4. Research papers most often use the abbreviation Pal-KTTKS, so searches under all three names return the same compound.

**What is the molecular weight of palmitoyl pentapeptide-4?**
PubChem lists palmitoyl pentapeptide-4 (CID 9897237) with a molecular weight of 802.1 g/mol and the molecular formula C39H75N7O10. Its CAS number is 214047-00-4 and its InChIKey is WSGCRSMLXFHGRM-DEVHWETNSA-N. Material supplied as a salt, such as an acetate, has a different bulk weight than the free peptide.

**How is Pal-KTTKS different from KTTKS?**
KTTKS is the unmodified five-residue procollagen fragment, while Pal-KTTKS carries a 16-carbon palmitoyl chain on its N-terminus. In hairless mouse skin, Pal-KTTKS was more stable than KTTKS and was detected in the stratum corneum, epidermis and dermis, whereas KTTKS was not detected in any skin layer under the same conditions.

**Is palmitoyl pentapeptide-4 FDA approved?**
No. Palmitoyl pentapeptide-4 is not approved by the FDA as a drug for any condition. It is a cosmetic ingredient, and cosmetic ingredients in the United States are not subject to FDA premarket approval. Its published human data come from a cosmetic trial on facial wrinkles, not from drug development studies.

**What does the research on palmitoyl pentapeptide-4 show?**
In a 12-week, placebo-controlled split-face trial in 93 women, Pal-KTTKS significantly reduced wrinkles and fine lines versus placebo. In fibroblasts it has increased collagen production, especially in liposomes, and reduced myofibroblast differentiation. Animal studies have tested it in burn-wound dressings and photoaging models, typically combined with delivery systems or other components.

**How is palmitoyl pentapeptide-4 different from palmitoyl tripeptide-1?**
Both are palmitoylated cosmetic peptides with the fatty acid chain on the N-terminus, but they carry different sequences. Palmitoyl pentapeptide-4 contains KTTKS, a fragment of type I procollagen, while palmitoyl tripeptide-1 contains GHK (glycyl-histidyl-lysine). Palmitoyl pentapeptide-4 has a larger published literature, including a placebo-controlled human trial.

## References

1. Robinson LR, Fitzgerald NC, Doughty DG, et al. Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin. International journal of cosmetic science 2005. PMID: 18492182
2. Park H, An E, Cho Lee AR. Effect of Palmitoyl-Pentapeptide (Pal-KTTKS) on Wound Contractile Process in Relation with Connective Tissue Growth Factor and α-Smooth Muscle Actin Expression. Tissue engineering and regenerative medicine 2017. PMID: 30603464
3. Tałałaj U, Uścinowicz P, Bruzgo I, et al. The Effects of a Novel Series of KTTKS Analogues on Cytotoxicity and Proteolytic Activity. Molecules (Basel, Switzerland) 2019. PMID: 31618846
4. Choi YL, Park EJ, Kim E, et al. Dermal Stability and In Vitro Skin Permeation of Collagen Pentapeptides (KTTKS and palmitoyl-KTTKS). Biomolecules & therapeutics 2014. PMID: 25143811
5. Vitali A, Paolicelli P, Bigi B, et al. Liposome Encapsulation of the Palmitoyl-KTTKS Peptide: Structural and Functional Characterization. Pharmaceutics 2024. PMID: 38399273
6. Osborne R, Hakozaki T, Laughlin T, et al. Application of genomics to breakthroughs in the cosmetic treatment of skin ageing and discoloration. The British journal of dermatology 2012. PMID: 22670614
7. Osborne R, Carver RS, Mullins LA, et al. Practical application of cellular bioenergetics to the care of aged skin. The British journal of dermatology 2013. PMID: 23786618
8. Errante F, Menicatti M, Pallecchi M, et al. Susceptibility of cosmeceutical peptides to proteases activity: Development of dermal stability test by LC-MS/MS analysis. Journal of pharmaceutical and biomedical analysis 2021. PMID: 33281001
9. Rasouli M, Shahghasempour L, Shirbaghaee Z, et al. Mesenchymal stem cell therapy using Pal-KTTKS-enriched carboxylated cellulose improves burn wound in rat model. Archives of dermatological research 2024. PMID: 38850353
10. Wang Z, Liu J, Chen Q, et al. Bioactive Glycyrrhizic Acid Ionic Liquid Self-Assembled Nanomicelles for Enhanced Transdermal Delivery of Anti-Photoaging Signal Peptides. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2025. PMID: 39783908