GHRP-6 is a synthetic hexapeptide compound belonging to the family of growth hormone secretagogues (GHSs). Its core mechanism of action involves specifically binding to the growth hormone secretagogue receptor (GHSR) in the pituitary gland and peripheral tissues, thereby promoting the synthesis and secretion of growth hormone (GH). By activating intracellular signaling pathways in pituitary GH-secreting cells, GHRP-6 enhances GH release and indirectly regulates insulin-like growth factor-1 (IGF-1) levels, thereby participating in growth, development, and metabolic homeostasis. It influences appetite and energy metabolism via paracrine or autocrine mechanisms, exerting nutritional effects on muscle and bone, including promoting muscle protein synthesis and improving bone metabolism. GHRP-6 plays a positive role not only in studying growth hormone deficiency mechanisms and GH-IGF-1 axis function but is also widely applied in metabolic and muscular health research. It is used to analyze its effects on muscle mass maintenance and fat metabolism, promoting tissue repair.
The peptide will be provided as lyophilized powder to ensure maximum stability.
What is GHRP-6?
GHRP-6 (Growth Hormone-Releasing Peptide 6) is a synthetic hexapeptide belonging to the Growth Hormone Secretagogues (GHS) family. Its core characteristic is the ability to specifically bind to the growth hormone secretagogue receptor (GHSR) in the pituitary gland and peripheral tissues, initiating related signaling pathways to regulate the synthesis and release of growth hormone (GH). It serves as a crucial substance for studying growth hormone regulatory mechanisms and associated physiological processes, currently primarily applied in the research field.
GHRP-6 Structure
Source: PubChem
Sequence: HWAWFK
Molecular Formula: C46H56N12O6
Molecular Weight: 873.0 g/mol
CAS Number: 87616-84-0
PubChem CID：9919153
Synonyms: Melanostatine 2ï¼›His(1)-lys(6)-ghrpï¼›GH-Releasing hexapeptide 6
GHRP-6 Research
What is the research background of GHRP-6?
Research on GHRP-6 originated from in-depth investigations into the regulatory mechanisms of growth hormone (GH). Early studies revealed that, beyond the natural growth hormone-releasing hormone (GHRH), the body possesses additional pathways regulating GH secretion, including receptors capable of specifically promoting GH release (i.e., the growth hormone secretagogue receptor, GHSR). To further unravel this regulatory pathway and identify tools for precise intervention in GH secretion, researchers began synthesizing compounds targeting GHSR. GHRP-6 emerged from this theoretical framework as a hexapeptide designed to activate the GHSR pathway, elucidating its role in regulating GH synthesis and release.
Concurrently, clinical and research demands for GH modulation tools propelled GHRP-6 studies. On one hand, diseases like growth hormone deficiency require more efficient GH regulation methods with unique mechanisms to supplement traditional interventions. On the other hand, researchers in fields like metabolism, muscle health, and tissue repair sought to explore related physiological processes by modulating the GH-IGF-1 axis. As a compound capable of precisely activating GHSR and regulating GH secretion, GHRP-6 became a crucial tool for studying the axis’s function and mechanisms in related domains, thereby driving investigations into its physicochemical properties and mechanisms of action.
What is the mechanism of action of GHRP-6?
Regulation of Growth Hormone Secretion
Non-Dependence on Traditional Hypothalamic Factors: GHRP-6 can specifically release growth hormone (GH) independently of the hypothalamic growth hormone-releasing hormone (GHRH) and somatostatin. This indicates it activates a pathway distinct from the classical hypothalamic regulatory pathway to stimulate GH secretion. For example, in certain experimental animal models and obese individuals, GHRP-6 demonstrates potent GH-releasing capacity unimpeded by conventional hypothalamic GHRH and somatostatin regulatory mechanisms[1].
Synergistic Action with GHRH: GHRP-6 and GHRH act on distinct receptors, exhibiting synergistic effects. Studies indicate that following meals, GH-secreting cells temporarily exhibit reduced responsiveness to GHRH; during this period, GHRP-6 potentiates GHRH-induced GH secretion. Intravenous GHRP-6 stimulates GH secretion in a dose-dependent manner. When combined with GHRH, both before and after meals, GHRP-6 synergistically induces substantial GH release. This combined effect has also been validated in cultured GH cells. Furthermore, GHRP-6 acts on the hypothalamus to stimulate GHRH secretion, thereby indirectly promoting GH release [2].
Effects on Autophagy and Apoptosis
Promotion of Autophagy: [D-Lys3]-GHRP-6, a variant of GHRP-6, is considered a highly selective growth hormone-releasing hormone receptor (GHSR) antagonist. Studies have shown that it enhances autophagy signaling in both normal and doxorubicin-damaged muscle, manifested by increased beclin-1 protein abundance and elevated LC3 II to LC3 I ratios. This indicates that GHRP-6-related variants play a crucial role in maintaining muscle cellular homeostasis and responding to injury by promoting autophagy to clear damaged cellular components, thereby facilitating normal cellular metabolism and functional recovery [3].
Inhibition of apoptosis: [D-Lys3]-GHRP-6 also reduced doxorubicin-induced apoptosis activation in muscle cells, with no histological abnormalities observed in treated muscle tissue. Concurrently, the increase in central nucleation of myofibers induced by doxorubicin was absent in [D-Lys3]-GHRP-6-treated muscles, suggesting its protective effect against doxorubicin damage. This maintains the normal physiological state of muscle cells by regulating apoptosis[3].
Regulation of Fibrosis-Related Gene Expression
Reduced Expression of Pro-Fibrotic Genes: In models such as liver fibrosis and skin wound healing, GHRP-6 exhibits anti-fibrotic properties. At the molecular level, it reduces the transcriptional expression of pro-fibrotic genes TGFB1 and CTGF. TGFB1 and CTGF play pivotal roles in fibrosis; their reduced expression helps inhibit excessive accumulation of extracellular matrix proteins, thereby alleviating fibrosis severity [4].
Induction of Anti-Fibrotic Gene Expression: GHRP-6 concurrently induces PPARG and MMP-13 gene expression. PPARG participates in regulating adipocyte differentiation and metabolism while exhibiting inhibitory effects on inflammation and fibrosis; MMP-13 degrades extracellular matrix components, aiding in maintaining normal tissue structure and function. Increased expression of both genes facilitates suppression of the pathological accumulation process of fibrosis [4].
Protective Mechanisms for Gastrointestinal Mucosa
Blocking Stress Signal Transduction: In a water immersion restraint stress (WRS)-induced gastric mucosal injury model, GHRP-6 exerts a protective effect. WRS transmits signals from skin stimulation via the vagus nerve to the central nervous system, leading to gastric mucosal injury. GHRP-6 prevents this damage, likely by blocking stress signal transmission, thereby reducing adverse vagus nerve stimulation to the gastric mucosa and averting mucosal injury [5].
Regulation of gastric acid secretion and other factors: WRS induces increased gastric acid secretion, whereas GHRP-6 may restore acid secretion to normal levels, thereby mitigating gastric acid damage to the mucosa. Additionally, GHRP-6 may exert indirect protective effects on the gastric mucosa by influencing plasma renin, endothelin-1, thromboxane B2, and gastric heat shock protein 70 in plasma, thereby indirectly protecting the gastric mucosa and maintaining its integrity and normal function [5].
Figure 1 Heart rate variability analyses showing the differences in mean R-R intervals, standard deviation of the normal-to-normal R-R intervals, and root mean square of successive differences of R-R intervals in different groups [5].
What are the applications of GHRP-6?
Anti-fibrotic effects
Liver fibrosis: In rat models of liver cirrhosis, both prophylactic and therapeutic use of GHRP-6 demonstrated significant efficacy. It reduced fibrotic nodules by over 75%, decreased cord thickness and cirrhotic nodule count by up to 60%, while also exerting pronounced hepatoprotective effects. At the molecular level, GHRP-6 decreased transcriptional expression of the pro-fibrotic genes TGFB1 and CTGF while inducing PPARG and MMP-13 gene expression—genes crucial for inhibiting pathological accumulation processes [4].
Skin fibrosis: In a rat simple wound model, GHRP-6 accelerated wound closure and reduced inflammatory infiltration. In a rabbit hypertrophic scar model, the peptide prevented keloid formation in over 90% of treated wounds, suggesting GHRP-6’s potential value in preventing and treating skin fibrosis-related disorders[4].
Stimulation of Growth Hormone Secretion
Effects on Normal Physiology: Intravenous administration of GHRP-6 stimulates growth hormone (GH) secretion in a dose-dependent manner. Following feeding, the response of GH cells to growth hormone-releasing hormone (GHRH) is temporarily diminished. However, co-administration of GHRP-6 with GHRH synergistically induces substantial GH release both before and after feeding, with equivalent effects observed in cultured GH cells. Furthermore, GHRP-6 acts on the hypothalamus to stimulate GHRH secretion[6].
Effects on Specific Disease States: In rats receiving chronic glucocorticoid therapy, GHRP-6 stimulates GH secretion but fails to reverse glucocorticoid-induced GH suppression. In patients with endogenous or exogenous glucocorticoid excess, those with endogenous hypercortisolemia exhibited diminished GH responses to both GHRP-6 and GHRH, whereas the response mechanism to GHRP-6 appeared preserved in patients with exogenous glucocorticoid excess[7,8].
Immunomodulatory Effects
In tilapia, GHRP-6 upregulates the transcriptional levels of three fish-specific bacteriocins (Oreochromicins I, II, and III) and granzyme in a tissue-dependent manner, regardless of Pseudomonas aeruginosa infection status. It also enhances serum antimicrobial activity (lysozyme and antiprotease activity), enhancing the in vitro antibacterial activity of tilapia gill mucus and serum samples against Pseudomonas aeruginosa and reducing bacterial load in vivo post-infection. This suggests GHRP-6 holds promise as an alternative therapeutic agent in aquaculture for stimulating the immune system of teleost fish against opportunistic bacteria [9].
Cardiac Protection Potential
Growth hormone-releasing peptides (GHRPs) stimulate growth hormone secretion and downstream axis activity, with their associated receptors widely distributed throughout the cardiovascular system. Early studies identified synthetic GHRPs as promising candidates for cardiac and cellular protection. Among these, GHRP-6—despite occasional and sporadic clinical interventions—holds potential for coherent clinical development based on its multifactorial mechanisms in myocardial infarction[10].
Conclusion
As a synthetic hexapeptide growth hormone secretagogue, GHRP-6 primarily regulates the GH-IGF-1 axis through specific binding to GHSR, demonstrating multifaceted value in physiological function modulation and disease research. GHRP-6 not only targets GH secretion to influence metabolic balance and tissue growth regulation but also exhibits effects in anti-fibrosis (liver, skin), cardioprotection (inhibiting myocardial apoptosis, improving cardiac function), and immunomodulation. It also serves as a critical research tool for elucidating GHSR function and GH regulatory mechanisms.
About The Author
The above-mentioned materials are all researched, edited and compiled by Nuvion Health.
Scientific Journal Author
L. Hernández is a researcher in the life sciences, engaged in academic work at universities or research institutes. His/her scholarly interests encompass areas related to animal health and molecular biology, with active involvement in interdisciplinary and international collaborations. As an author of multiple peer-reviewed publications, L. Hernández has contributed to the advancement of knowledge in the field and maintains a recognized presence in the scientific community. L. Hernández is listed in the reference of citation [9].
Relevant Citations
[1] Micic D, Mallo F, Peino R, et al. Regulation of growth hormone secretion by the growth hormone releasing hexapeptide (GHRP-6). J Pediatr Endocrinol 1993; 6(3-4): 283-289.
[2] McMahon CD, Chapin LT, Radcliff RP, Lookingland KJ, Tucker HA. GH-releasing peptide-6 overcomes refractoriness of somatotropes to GHRH after feeding. Journal of Endocrinology 2001; 170(1): 235-241.DOI: 10.1677/joe.0.1700235.
[3] Yu AP, Pei XM, Sin TK, et al. [D-Lys3]-GHRP-6 exhibits pro-autophagic effects on skeletal muscle. Molecular and Cellular Endocrinology 2015; 401: 155-164.DOI: 10.1016/j.mce.2014.09.031.
[4] Mendoza-Mari Y, Fernández Mayola M, Vázquez-Blomquist D, et al. GHRP-6, a novel candidate for prevention and treatment of fibrotic disorders. Biotecnologia Aplicada 2017; 34: 2501-2504.
[5] Guo S, Gao Q, Jiao Q, Hao W, Gao X, Cao JM. Gastric mucosal damage in water immersion stress: mechanism and prevention with GHRP-6. World Journal of Gastroenterology 2012; 18(24): 3145-3155.DOI: 10.3748/wjg.v18.i24.3145.
[6] McMahon CD, Chapin LT, Radcliff RP, Lookingland KJ, Tucker HA. GH-releasing peptide-6 overcomes refractoriness of somatotropes to GHRH after feeding. Journal of Endocrinology 2001; 170(1): 235-241.
[7] Voltz DM, Piering AW, Magestro M, Giustina A, Wehrenberg WB. Effect of GHRP-6 and GHRH on GH secretion in rats following chronic glucocorticoid treatment. Life Sciences 1995; 56(7): 491-497.DOI: 10.1016/0024-3205(94)00478-b.
[8] Borges MH, DiNinno FB, Lengyel AM. Different effects of growth hormone releasing peptide (GHRP-6) and GH-releasing hormone on GH release in endogenous and exogenous hypercortisolism. Clinical Endocrinology 1997; 46(6): 713-718.DOI: 10.1046/j.1365-2265.1997.1981008.x.
[9] Hernández L, Camacho H, Nuñez-Robainas A, et al. Growth hormone secretagogue peptide-6 enhances oreochromicins transcription and antimicrobial activity in tilapia (Oreochromis sp.). Fish & Shellfish Immunology 2021; 119: 508-515.DOI: 10.1016/j.fsi.2021.08.011.
[10] Berlanga-Acosta J, Nieto GEG, Pez-Mola ELO, Nez LISH. Growth hormone releasing peptide-6 (GHRP-6) and other related secretagogue synthetic peptides: A mine of medical potentialities for unmet medical needs. Integrative Molecular Medicine 2016; 3: 616-623. https://api.semanticscholar.org/CorpusID:45189287.
