Glycomacropeptide (GMP): A Sustainable Bioactive Peptide for Atopic Dermatitis Management and Skin Anti-Aging
Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease globally, affecting 15%–30% of children and 2%–10% of adults. In the US alone, associated treatment costs exceed $5 billion annually. AD also significantly increases the risk of comorbidities like asthma and allergic rhinitis, severely impacting patients' quality of life. The chronic inflammation associated with AD accelerates collagen degradation, wrinkle formation, and loss of skin elasticity, promoting premature skin aging. Current standard treatments, primarily corticosteroids, can cause adverse effects with long-term use, such as skin atrophy, telangiectasia, dyspigmentation, and increased infection risk. They may also further exacerbate collagen degradation and accelerate skin aging. In children, they can lead to growth retardation and adrenal suppression. These limitations restrict long-term clinical use and impose a heavy physiological and psychological burden on patients.
Glycomacropeptide (GMP), a milk-derived bioactive peptide generated by the enzymatic hydrolysis of κ-casein by chymosin during cheese production, is a novel natural active ingredient with both therapeutic and skincare value. It possesses anti-inflammatory, antioxidant, and skin barrier repair properties. Thanks to its amphiphilic structure (conferring natural emulsifying ability), its relatively low molecular weight (enabling good penetration), its high oral bioavailability, and its excellent safety profile, GMP can multi-target the pathological processes of AD while protecting collagen integrity by inhibiting oxidative stress and inflammatory aging. Simultaneously, it enables the high-value utilization of dairy by-products, offering a new breakthrough direction in the fields of inflammatory skin disease treatment and anti-aging skincare.
A review published in the Journal of Immunotoxicologysystematically integrates existing in vitro, in vivo, and preliminary clinical evidence. It comprehensively elaborates on the physicochemical properties of GMP, its mechanisms of action concerning skin health, and its potential for AD management and skin anti-aging. It also provides an in-depth analysis of current research gaps and translational challenges in the field, clarifying future R&D directions. This offers comprehensive scientific reference for the R&D and application of GMP in dermatological therapy and cosmetics.
1. Fundamental Physicochemical Properties and Applications of GMP
1.1 Physicochemical Properties
Glycomacropeptide is a heterogeneous mixture of peptide fragments released into whey during cheese production through the hydrolysis of κ-casein by chymosin, with a molecular weight of approximately 7-9 kDa. Its isoelectric point ranges from 3.5 to 4.0, influenced by its degree of glycosylation. The amino acid composition of GMP is notable: it is rich in branched-chain amino acids like leucine and isoleucine, while its phenylalanine content is extremely low (below 10 ppm by HPLC), making it theoretically suitable for individuals with phenylketonuria. The high sialic acid content in the peptide confers a negative charge at physiological pH. This characteristic, along with its phosphorylation sites and glycosylation structure, determines its solubility, stability, and ability to interact with biomacromolecules. Additionally, the GMP molecule features both hydrophilic carbohydrate chains and hydrophobic peptide regions, presenting typical amphiphilicity, which grants it natural emulsifying capacity useful for stabilizing oil-in-water or water-in-oil emulsion systems.
1.2 Application Advantages
From a production standpoint, GMP can be prepared at scale using continuous ultrafiltration technology. The peptide structure offers some flexibility; by adjusting process parameters like pH, processing time, and agitation speed, the molecular weight distribution can be tailored to a certain extent to suit different skincare or pharmaceutical application needs. Regarding delivery, its relatively low molecular weight gives it good potential for skin penetration when incorporated into rationally designed topical delivery systems. For oral administration, GMP is structurally stable in the gastrointestinal tract with high absorption efficiency, and it has a neutral flavor without bitterness, eliminating the need for additional de-bittering steps. Therefore, it can be developed both as topical creams/emulsions and oral beauty supplements. Furthermore, GMP maintains structural stability across a wide pH range and under high temperatures, a property that makes it compatible with various skincare formulation processes like gels, creams, and lotions.
2. Mechanisms of Action in Atopic Dermatitis Management
The pathology of atopic dermatitis is complex, involving multiple interconnected aspects: skin barrier defect, immune dysregulation, oxidative stress, and microbial dysbiosis. Existing research indicates that glycomacropeptide can systemically intervene in this pathological network through multi-target, multi-pathway actions. Its core mechanisms and supporting experimental evidence primarily encompass the following five aspects:
2.1 Modulating Immune Dysregulation and Inhibiting Th2-type Inflammation
GMP effectively regulates the characteristic Th2-type immune response imbalance in AD. In animal models of AD, both preventive and therapeutic administration of GMP significantly inhibits key inflammatory effector cells. For example, preventive administration reduced eosinophil counts by 94.47% and mast cells by 61.51%; therapeutic administration also achieved reductions of 78.71% in eosinophils and 39.59% in mast cells. Simultaneously, GMP substantially lowers serum levels of IgE, a core mediator of allergy (86.53% reduction preventively, 63.68% therapeutically), and dose-dependently inhibits the production of Th2-related pro-inflammatory cytokines like IL-4, IL-5, and IL-13, while upregulating the expression of the anti-inflammatory cytokine IL-10 (a 4.68-fold increase with preventive administration), thereby helping to re-establish immune homeostasis. At the initiation of inflammation, GMP also effectively inhibits the overexpression of "alarmins" (e.g., TSLP, IL-33) and chemokines (e.g., TARC, MDC) produced by keratinocytes stimulated by TNF-α and IFN-γ. Notably, its anti-inflammatory effect is inflammation-dependent, showing minimal impact on normal, resting cells, indicating high selectivity and safety.
2.2 Counteracting Oxidative Stress and Protecting Keratinocytes
Oxidative stress is a significant driver of skin damage in AD. GMP exerts antioxidant effects by scavenging reactive oxygen species and chelating pro-oxidant metal ions. In an AD-like model using human immortalized keratinocytes (HaCaT), GMP concentration-dependently reversed the abnormal elevation of various oxidative stress markers. Specifically, 6.3 mg/mL and 25 mg/mL GMP reduced nitric oxide levels by 50% and 83.2%, respectively, restored lipid hydroperoxide concentrations to near-normal cell levels, and inhibited the overexpression of the oxidative stress response gene HMOX1 by 70.5% and 61.6%, respectively. Furthermore, GMP significantly inhibited keratinocyte apoptosis induced by chemical irritants like DNCB or hydrogen peroxide, with 25 mg/mL concentration nearly completely restoring the viability of damaged cells, thereby protecting the cellular foundation of the skin barrier.
2.3 Modulating Skin and Gut Microbiota
Microbial dysbiosis is a significant trigger in the onset and progression of AD. GMP shows potential in modulating both skin and gut microbiota. At the gut level, GMP can act as a prebiotic, selectively promoting the growth of beneficial bacteria like Bifidobacterium and Lactobacillus, and increasing the secretion of the immunoregulatory factor TGF-β, thereby enhancing immune tolerance. Studies indicate that this modulatory effect on gut microbiota can be sustained even after GMP supplementation is stopped. Locally on the skin, GMP significantly reduces the relative abundance of potential pathogens like Staphylococcus aureusand Staphylococcus epidermidison the skin of AD model rats, helping to restore skin micro-ecological balance and reduce inflammation and itching exacerbated by pathogen colonization. This dual regulation of the "gut-skin axis" may be one mechanism through which GMP exerts its immunomodulatory effects.
2.4 Repairing the Skin Barrier and Alleviating Core Clinical Symptoms
Impaired skin barrier function is a core feature of AD. GMP synergistically promotes barrier repair and alleviates related symptoms through multiple pathways. At the protein level, GMP effectively maintains the expression of the key barrier protein filaggrin. In AD animal models, preventive GMP administration completely prevented a 69.13% decrease in filaggrin levels, while therapeutic administration even increased its expression by 1.84-fold, thereby enhancing skin hydration and mechanical resilience. Structurally, GMP significantly improves the pathological epidermal hyperplasia (acanthosis) caused by AD, likely by downregulating cytokines like IFN-γ. Preventive and therapeutic administration reduced epidermal thickness by 46.51%–95.6% and 28.96%–54.55%, respectively. Regarding inflammatory symptoms, GMP inhibits inflammation-mediated increases in vascular permeability, thereby alleviating edema; preventive administration reduced ear edema by 97.03%. Notably, preventive GMP administration reduced scratching behavior in AD model animals by over 99%, nearly eliminating itching. This mechanism is associated with downregulating the itch mediator IL-33 and inhibiting S. aureuscolonization.
2.5 Promoting Wound Healing
AD patients often experience recurrent scratching due to intense itching, leading to skin breakdown, crusting, and delayed healing. In vitro experiments confirm that GMP significantly promotes keratinocyte migration, with wound-healing effects comparable to epidermal growth factor. GMP treatment achieved approximately 30% wound closure within 24 hours, and by 72 hours, wound closure rates reached 51.66%–56.08%, significantly outperforming the untreated control group. This ability to promote skin lesion repair helps break the "itch-scratch-barrier damage-worsened inflammation" vicious cycle in AD.
3.Mechanisms for Delaying Skin Aging
Atopic dermatitis and skin aging share significant overlaps in pathological mechanisms, both involving core processes like chronic inflammation and oxidative stress. Therefore, while intervening in AD, glycomacropeptide can also delay skin aging through multi-target actions, achieving a synergistic effect of treatment and anti-aging. The mechanisms primarily include the following two aspects:
3.1 Inhibiting Inflammaging
Chronic low-grade inflammation is a key driver of both intrinsic skin aging and photoaging. The persistent inflammatory state in AD exacerbates this process, termed "inflammaging." GMP can reduce inflammatory signals upstream by inhibiting the sustained secretion of key pro-inflammatory cytokines like TNF-α and IL-6. This helps lower the inflammation-mediated expression of matrix metalloproteinases, thereby reducing the degradation of extracellular matrix components like collagen and elastin, preventing wrinkle formation and skin laxity. Additionally, GMP can mitigate the acute inflammatory response to UV irradiation that drives photoaging, helping delay associated issues like hyperpigmentation and skin roughness.
3.2 Maintaining Skin Structural Integrity and Cellular Vitality
GMP maintains youthful skin structure through multiple combined pathways. Firstly, its antioxidant capacity directly scavenges reactive oxygen species, protecting the collagen network and other extracellular matrix components from oxidative damage. Secondly, it inhibits excessive keratinocyte apoptosis, ensuring normal epidermal turnover. Importantly, GMP exhibits a bidirectional regulatory effect on epidermal thickness: it can alleviate pathological thickening in AD while potentially improving the epidermal atrophy associated with natural aging or photoaging, thereby helping maintain normal skin thickness, structure, and elasticity. Furthermore, GMP's promotion of filaggrin expression can long-term consolidate the skin barrier function, reduce transepidermal water loss, and directly improve aging-related skin dryness and fine lines.
4.Safety Evaluation and Sustainability Value
4.1 Safety Evaluation
Existing in vitro evidence indicates that GMP shows no cytotoxicity towards normal human keratinocytes across a broad concentration range of 0.01 to 25 mg/mL, with no impact on cell viability. At concentrations effective for its anti-inflammatory and antioxidant bioactivities, no adverse effects on normal skin cells have been observed. Additionally, due to its composition being virtually free of phenylalanine, GMP is suitable for individuals with phenylketonuria. To date, research has not identified a clear sensitization risk, providing a preliminary safety basis for its topical and oral application. However, the review also notes the current lack of long-term human safety data, and systematic sensitization assessments for sensitive populations like AD patients require further substantiation and completion.
4.2 Sustainability Value
GMP is primarily sourced from whey, a by-product of the cheese industry. Its development and application represent the high-value utilization of dairy processing waste, not only reducing waste discharge but also aligning with the principles of a circular economy and the UN Sustainable Development Goal (SDG) of "Responsible Consumption and Production." Simultaneously, as a naturally derived active ingredient, its inherent functional properties like emulsification can help reduce the use of synthetic emulsifiers, preservatives, and other additives in cosmetics, thereby lowering the associated environmental burden from chemical production. This further resonates with other SDGs like "Good Health and Well-being" and "Life on Land," positioning GMP as a representative functional ingredient embodying the "green beauty" concept.
5.Current Limitations and Future Development Directions
5.1 Main Bottlenecks
Current research on GMP faces several significant gaps. The foremost issue is the lack of robust human clinical trial evidence. Most existing results are from cell and animal studies, making it impossible to determine its actual efficacy in humans or the optimal usage regimen. Secondly, some of its mechanisms of action remain insufficiently clear, such as how it influences the skin via the "gut-skin axis" and the specific pathways for promoting wound healing. Furthermore, practical product development faces difficulties, such as enhancing transdermal absorption for topical applications and ensuring effective utilization for oral formulations. The industry also lacks unified quality standards. Finally, there is a scarcity of long-term safety data, particularly concerning risk assessments for sensitive populations like dermatitis patients.
5.2 Future Directions
Addressing the above bottlenecks, the core future research priorities include: ① Prioritizing well-designed human clinical trials to clarify the clinical efficacy, dose-response relationship, and long-term safety of GMP for AD patients, while validating its skin anti-aging effects in humans. ② Deepening molecular mechanism research to identify the core molecular targets of GMP's anti-inflammatory, antioxidant, and microbiota-modulating actions, and to elucidate the specific pathways of its "gut-skin axis" regulation. ③ Optimizing formulation processes and delivery systems to develop highly stable, high-bioavailability dedicated formulations for topical and oral use, expanding its application scenarios in medical foods, efficacy-driven skincare, and as an adjuvant in dermatological therapy. ④ Establishing unified quality standards and production specifications, improving purity testing and peptide characterization systems for GMP, and systematically conducting sensitization and long-term safety assessments for sensitive populations, laying the groundwork for industrial translation.
6. Summary
Atopic dermatitis and skin aging share core pathological mechanisms like chronic inflammation, oxidative stress, and barrier impairment. Long-term use of current mainstream therapies is limited by significant side effects and the potential to accelerate skin aging. Glycomacropeptide, a natural bioactive peptide derived from whey by-products, demonstrates unique potential in addressing this dual challenge. It possesses multiple biological activities, including anti-inflammatory, antioxidant, barrier repair, microbiota modulation, and wound healing promotion. This allows it to multi-target the pathological processes of AD and, by inhibiting inflammatory aging and oxidative damage, synergistically achieve both dermatitis management and skin anti-aging.
Furthermore, originating from dairy industry by-products, GMP aligns with circular economy and sustainable development principles. Its favorable safety profile and physicochemical properties suitable for both topical and oral application form a foundation for its use in dermatological adjuvant therapy and efficacy-driven skincare. Currently, research in this field remains predominantly at the preclinical stage, facing challenges such as insufficient human evidence, the need for deeper mechanistic understanding, and a lack of industrial standards. Advancing through rigorous clinical validation, in-depth mechanistic studies, optimization of formulation processes, and establishment of unified standards holds promise for positioning glycomacropeptide as a safer, more environmentally friendly, and effective solution for skin health.
Original article：
Majidinia, Lida, Ladan Majidinia, and Ahmad Kalbasi-Ashtari. "The beneficial properties of glycomacropeptide in management of atopic dermatitis and extenuating skin aging." Journal of Immunotoxicology 23.1 (2026): 2619154.