Abstract
Ergothioneine (EGT) is a multifunctional antioxidant exhibiting reactivity toward reactive oxygen and nitrogen species, metal-chelating capacity, and transporter-mediated cellular accumulation. Edible mushrooms are rich dietary sources, while microbial biosynthesis offers opportunities for sustainable production. This critical narrative review examines EGT chemistry, biological mechanisms, production, and applications within food systems as well as cosmeceutical/pharmaceutical fields, focusing on studies reporting production, preservation, or formulation outcomes. Special emphasis is placed on inhibiting lipid oxidation, enzymatic browning, and pigment degradation in meat, seafood, and plant-based products. Advances in delivery systems, including nanocarriers designed to enhance stability, bioavailability, and functional performance in fortified foods and active packaging are discussed. However, heterogenous studies, limited clinical evidence, and uncertain long-term safety constrain its translation, and limit firm conclusions of this review. Future priorities include standardization of methods to measure EGT in food, well-designed clinical trials, and regulatory frameworks for nanoformulated EGT, to support food and nutraceutical applications.
Keywords: Ergothioneine, Food industry, Nano-delivery, Antioxidant, Mushroom extract, OCTN1
Highlights
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EGT exhibits antioxidant and metal-chelating properties.
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Microbial biosynthesis offers alternative route for EGT production.
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Delivery systems for EGT include coatings, films, emulsions and nanocarriers.
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Standardized analysis and controlled trials are priorities for translation of EGT.
1. Introduction
New trends in food and nutrition such as food fortification and precision nutrition have recently emerged, in parallel with increased consumer awareness and demand for plant-based healthy food products, particularly natural antioxidants and nutraceuticals. Food fortification with natural antioxidants and nutraceuticals may contribute to improved nutritional status and reduced risk of chronic and age-related diseases (Hossain et al., 2025).
Plants and their by-products are not only a rich source of functional ingredients for nutrition, but they can also be used as natural preservatives to prolong the shelf life of food products such as fruits, vegetables, seafood, and meat by mitigating oxidative stress, in response to the global need for chemical-free and clean-label foods (Parveen et al., 2025). Preservation is achieved by inhibiting lipid oxidation and discoloration, exerting antimicrobial activities, and maintaining the freshness and quality of the product. Agricultural products and by-products of mushrooms are valuable resources in this regard, owing to their abundance, low cost, sustainability, and richness in bioactive compounds (Atallah et al., 2021; Luo & Chen, 2024; Teshome et al., 2022).
Despite their merits, there are some challenges to the use of these functional ingredients, particularly related to their solubility and stability under environmental, processing, and physiological conditions (McClements, 2018), thereby affecting the bioavailability and desired food product quality during the shelf life. Nanoencapsulation of functional molecules is a potential solution to these challenges, enhancing stability, bioavailability, efficacy, processing performance, and shelf-life, as well as resistance to environmental impacts (Ashraf et al., 2019; Han et al., 2025; Hao et al., 2026; Rezagholizade-Shirvan et al., 2024; Wen, Tang, et al., 2025; Yu et al., 2023).
Among the promising bioactive compounds, ergothioneine (EGT) (Fig. 1) stands out as a particularly distinctive bioactive molecule, known for being “longevity-associated”. EGT is a sulfur-containing derivative of the amino acid histidine, which was first isolated from the ergot fungus Claviceps purpurea in 1909 (Cheah & Halliwell, 2012). Neither humans, animals, nor plants can synthesize it, yet they acquire it from the environment and through their diet. EGT is biosynthesized exclusively by certain fungi and bacteria, such as cyanobacteria and mycobacteria (Cheah & Halliwell, 2012). Plants obtain EGT from microorganisms in the soil and/or from symbiotic organisms, and in turn supply EGT to humans and animals through the diet (Wijesekara & Xu, 2024). Edible mushrooms are the richest known dietary sources of EGT, and it is only present in trace amounts in other dietary sources (Zhang, Liu, et al., 2025; Zhang, Ning, et al., 2025). The content of EGT varies among mushroom species and strains, with Boletus edulis (Porcini) having one of the highest recorded yields, up to 7000 mg/kg dry weight (Kalaras et al., 2017). Factors such as cultivation practices, harvesting, storage conditions, processing, and extraction were also reported to affect EGT content. In order to obtain EGT in a sustainable manner, biosynthesis from fungi and bacterial cultures has been identified as the best and most cost-effective methods, avoiding the complexity of cultivation/harvesting and chemical synthesis (Sato et al., 2025). Synthetic L- ergothioneine has been evaluated by the European Food Safety Authority (EFSA) and is permitted as a novel food ingredient at specified intake levels (EFSA Panel on Dietetic Products et al., 2016), and is also recognized under Generally Recognized as Safe (GRAS) status by the U.S. Food and Drug Administration for use in conventional foods and dietary supplements. It is considered a longevity vitamin in the literature with beneficial health effects, such as anti-inflammatory, neuroprotective, cardioprotective, anticancer, and anti-aging effects, suggesting potential roles in reducing the risk of chronic diseases (Beelman et al., 2022; Borodina et al., 2020; Fu et al., 2025; Harasym et al., 2025; Zhang, Liu, et al., 2025; Zhang, Ning, et al., 2025). Furthermore, EGT has been extensively tested for food preservation and color stabilization owing to the prevention of lipid, protein, and other molecules oxidation in the food matrix (Bao et al., 2008; Kitsanayanyong & Ohshima, 2022).
Fig. 1.
Chemical structure of EGT. EGT is a sulfur-containing histidine derivative characterized by a thioimidazole ring and an amino acid side chain. The molecule exhibits thiol–thione tautomerism, with the thione form predominating under physiological conditions, and exists predominantly as a zwitterion at physiological pH. These structural features contribute to its distinctive redox and antioxidant properties. Created in BioRender. Aly, M. (2026) https://BioRender.com/osrtfbw.
This review critically examines the relationship between the unique chemical structure of EGT and its exceptional antioxidant activity, integrating current evidence on its health-promoting effects and functional performance in food systems (Fig. 2). Furthermore, this review also discusses emerging nanotechnology-based delivery strategies as innovative solutions to enhance its formulation stability, bioavailability, and technological applicability, while identifying key challenges and future research directions for its sustainable incorporation into functional foods. This is a narrative review that employs a comprehensive approach to collect and analyze studies investigating the applications of EGT as a natural extract, formulation, or as part of a nano-delivery system in the food, cosmetic, and pharmaceutical industries. It also highlights other promising applications in various sectors. Studies were gathered from four databases: Scopus, PubMed, Google Scholar, and ScienceDirect, using the search term “Ergothioneine” to ensure a thorough review. The review includes all research articles published between 2008 and September 2026 that demonstrate the use of EGT or EGT-rich mushroom extracts in the food and pharmaceutical industries. Only studies published in English were considered. References for other sections were selected based on their recency, quality, and peer-reviewed status.
Fig. 2.
Human health and food system benefits for EGT. Created in Biorender, Aly, M. (2026) https://BioRender.com/p3n7jeh.
2. Chemistry, biology, and health relevance of EGT
EGT exhibits a unique redox behavior governed by its unique thione–thiol chemistry. In aqueous solution, EGT exists predominantly in the thione form, stabilized by resonance interactions within the 2-thioimidazole ring. Unlike classical thiols, its sulfur atom participates in extensive charge delocalization, resulting in selective redox reactivity (Yadan, 2022; Zhang, Liu, et al., 2025; Zhang, Ning, et al., 2025). Although the formal pKa of the thiol group is high (≈11), the predominance of the thione tautomer under physiological conditions further limits the availability of a reactive thiolate species. Consequently, EGT does not function as a rapid, chain-breaking antioxidant but instead displays preferential reactivity toward highly aggressive oxidants such as hydroxyl radicals, hypochlorous acid, singlet oxygen, and peroxynitrite, while reacting slowly with hydrogen peroxide and exhibiting negligible interaction with superoxide or molecular oxygen. This chemically restrained yet targeted reactivity underlies its role as a stable cytoprotective molecule capable of mitigating severe oxidative insults without perturbing basal redox homeostasis (Halliwell et al., 2016; Wen, Chen, et al., 2025; Yadan, 2022).
Beyond radical scavenging, EGT contributes to redox regulation through coordination of certain transition metal ions, particularly copper and iron, which are capable of catalyzing ROS formation. By interacting with redox-active metals, EGT may reduce metal-driven oxidative reactions, including copper-mediated DNA and protein oxidation and iron-dependent Fenton chemistry. This mechanism may be particularly relevant in tissues with high iron content, such as liver and kidney, where dysregulated metal homeostasis contributes to oxidative stress. Although the metal-binding affinity of EGT is moderate compared with classical chelators, its coordination chemistry may influence redox cycling and, in some experimental systems, modulate the activity of selected metalloenzymes, thus inhibiting the oxidation of metals which consequently cause ROS generation. These properties distinguish EGT from purely chain-breaking antioxidants and support its role as a modulator of metal-associated oxidative processes (Cheah & Halliwell, 2012; Fu & Shen, 2022; Kerley et al., 2018; Yadan, 2022; Zhang, Liu, et al., 2025; Zhang, Ning, et al., 2025).
EGT has been reported to protect against radiation-induced oxidative stress, including damage triggered by ultraviolet (UV) and gamma radiation. In addition, EGT can chemically react with highly reactive oxidants, thereby attenuating oxidative damage to lipids, proteins, and nucleic acids while exhibiting greater oxidative stability compared with many conventional thiol antioxidants (Cheah & Halliwell, 2012; Halliwell et al., 2016).
EGT was also reported to accumulate in tissues characterized by high metabolic and oxidative activity via the organic cation transporter novel type 1 (OCTN1) transporter, and mitigate mitochondrial oxidative damage. By reducing lipid peroxidation and protein oxidation, EGT preserves mitochondrial integrity and attenuates ROS-induced mitochondrial dysfunction, thereby supporting cellular energy metabolism. In vitro and in vivo studies further suggest that EGT can reduce apoptotic signaling, and provides valuable therapeutic benefits under conditions of ischemia–reperfusion injury, and aging. Beyond its direct antioxidant activity, EGT has been shown to modulate redox-sensitive signaling pathways, including Nrf2-mediated gene expression, leading to increased expression of cytoprotective phase II enzymes such as quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1). EGT has also been reported to influence the activity or expression of additional antioxidant enzymes while suppressing pro-oxidant pathways, collectively contributing to improved cellular redox homeostasis (Abdi Syahputra et al., 2025; Apparoo et al., 2022; Cheah & Halliwell, 2012; Fu & Shen, 2022; Harasym et al., 2025; Kerley et al., 2018). However, although EGT's direct antioxidant activity is well-characterized, the relative contributions of direct scavenging and indirect redox signaling to its biological activities remain incompletely resolved and are dependent on the experimental model and conditions.
Oxidative stress and inflammation are tightly interconnected processes, as ROS can activate redox-sensitive signaling pathways involved in inflammatory responses. EGT has been reported to modulate both oxidative and inflammatory processes (Fig. 3), partly through attenuation of NF-κB activation, leading to reduced expression of pro-inflammatory mediators such as TNF-α, IL-1β, and IL-6 in experimental models. In addition, the expression of the EGT transporter OCTN1 has been shown to increase in certain immune cells under inflammatory conditions, potentially enhancing intracellular accumulation of EGT. These observations support the hypothesis that EGT may function as a stress-responsive cytoprotective molecule with immunomodulatory properties, particularly in the context of chronic inflammatory disorders (Abdi Syahputra et al., 2025; Halliwell et al., 2023; Wen, Chen, et al., 2025).
Fig. 3.
Antioxidant and anti-inflammatory properties of EGT. Reproduced from Harasym et al. (2025), Molecules 30(23):4621, under the terms of the CC BY license.
The biological distribution and cellular availability of EGT are largely determined by the highly specific transporter OCTN1, encoded by the SLC22A4 gene. OCTN1 mediates the uptake and tissue accumulation of EGT in erythrocytes, liver, kidney, brain, and other metabolically active tissues. Genetic polymorphisms in SLC22A4 influence EGT transport efficiency and have been associated with susceptibility to certain inflammatory disorders. EGT exhibits a relatively long biological half-life, reflecting both its intrinsic chemical stability and transporter-mediated retention. Its zwitterionic nature and resistance to auto-oxidation contribute to its persistence in biological systems, allowing substantial intracellular accumulation in selected tissues (Cheah & Halliwell, 2012; Halliwell et al., 2016; Harasym et al., 2025; Zhang, Liu, et al., 2025; Zhang, Ning, et al., 2025).
Preclinical studies have demonstrated protective effects of EGT in cardiovascular disease, neurodegeneration, metabolic disorders, renal injury, and inflammatory conditions (Table 1, Table 2). These benefits have been associated with attenuation of oxidative stress, preservation of mitochondrial function, and modulation of inflammatory signaling pathways. Observational and clinical studies have further reported associations between higher dietary intake or circulating EGT levels and reduced incidence of chronic disease markers, improved cognitive performance, and indicators of healthy aging. Conversely, lower EGT concentrations have been observed in several pathological states, suggesting that circulating levels may reflect redox imbalance in disease conditions (Abdi Syahputra et al., 2025; Cheah and Halliwell, 2012, Cheah and Halliwell, 2021; Nakamichi et al., 2022).
Table 1.
Neurological and cardiometabolic effects of ergothioneine.
| Disease/ Condition | Mechanism and Efficacy of EGT | References |
|---|---|---|
| Neurodegenerative Diseases |
|
(Abdi Syahputra et al., 2025;Cheah & Halliwell, 2021;Fu & Shen, 2022;Halliwell et al., 2018;Nakamichi et al., 2022). |
| Cardiovascular Diseases |
|
(Fu & Shen, 2022;Halliwell et al., 2018). |
| Liver Diseases |
|
(Cheah & Halliwell, 2021;Fu & Shen, 2022;Wen, Chen, et al., 2025). |
| Diabetes Mellitus |
|
(Fu & Shen, 2022;Wen, Chen, et al., 2025). |
Table 2.
Other biological activities of ergothioneine.
| Disease/ Condition | Mechanism and Efficacy of EGT | References |
|---|---|---|
| Cancer |
|
(Abdi Syahputra et al., 2025; Cheah & Halliwell, 2021;D'Onofrio et al., 2022;Wen, Chen, et al., 2025). |
| Skin Disorders |
|
(Abdi Syahputra et al., 2025;Liu, Tang, Wang, Jiang, Zhang, & Wang, 2023;Wen, Chen, et al., 2025). |
| Ocular Disorders |
|
(Cheah & Halliwell, 2021;Halliwell et al., 2018). |
| Pre-eclampsia and Reproductive Health |
|
(Cheah & Halliwell, 2021;Fu & Shen, 2022;Kerley et al., 2018;ÖZtürkler et al., 2010;Zullo et al., 2016). |
| Aging and Cellular Senescence |
|
(Abdi Syahputra et al., 2025;Apparoo et al., 2022;Roda et al., 2022;Weng et al., 2024). |
The biological and functional relevance of EGT has increased interest in its use in food and nutraceutical applications. Meeting this demand requires reliable production methods that can provide EGT with suitable quality, purity and sustainability.
3. Sustainable production
Fungi and certain bacteria synthesize EGT exclusively, while higher plants and animals acquire it only through dietary intake or ecological transfer because they lack the biosynthetic machinery (Liu & Luo, 2026; Yan et al., 2026; Zheng et al., 2026). Edible mushrooms represent the richest dietary reservoir, whereas fruits, vegetables, grains, and animal products generally contain trace amounts acquired indirectly via soil microorganisms or the food chain (Yan et al., 2026;Zhang, Liu, et al., 2025 ; Zhang, Ning, et al., 2025 ; Zheng et al., 2026). Content varies substantially with species, strain, cultivation substrate, light exposure, and post-harvest handling (Harasym et al., 2025).
Apart from EGT intake from food, EGT can be produced through three main methods; natural extraction, chemical synthesis, and microbial fermentation. Natural extraction from mushrooms via reflux, ultrasonic, microwave, or enzymatic digestion is simple and gives a naturally sourced product but recovery, yield, cost depend on the extraction method and variable raw material supply (Zhang, Liu, et al., 2025; Zhang, Ning, et al., 2025; Zheng et al., 2026). A notable variant of this route valorizes mushroom processing residues, including spent mushroom substrate (SMS), stems, and culls, as potential sources of EGT. Recovering EGT from these residuals via green extraction techniques (hot-water, ultrasound-, microwave-, and high-hydrostatic-pressure-assisted methods), coupled with membrane separation and chromatographic purification, converts an otherwise discarded waste stream into a viable feedstock, aligning natural extraction with circular bioeconomy principles while partially offsetting its raw-material limitations (Harasym et al., 2025). Therefore, a circular production model is expected to recover EGT from mushroom-processing residues while retaining the remaining material, however SMS, stems and rejected fruiting bodies should be evaluated separately, since their composition and recoverable EGT content might vary. Evaluation of sustainability should take into account the recovery yield, product purity, solvent use, water and energy consumption, and management of the remaining residues. Therefore, while offering an opportunity to reduce wastes, by-product valorization does not necessarily establish an environmental advantage over other production routes.
Chemical synthesis constructs the imidazole–thiol scaffold from histidine or glyoxal/thiourea precursors through multi-step reactions, enabling scalable, high-purity production but requiring potentially hazardous reagents, such as heavy-metal catalysts, possibly generating optical isomers, while environmental and consumer-acceptance concerns may affect its industrial application (Liu & Luo, 2026; Zheng et al., 2026). Microbial fermentation offers an alternative to extraction and chemical synthesis, with potential advantages in scalability and sustainability, but it still requires substantial engineering to overcome metabolic and process constraints (Liang et al., 2025; Liu & Luo, 2026). It is also a promising route for EGT biosynthesis at industrial scale because it combines renewable feedstocks and controlled fermentation, while reducing dependence on mushroom raw materials. However, its main challenge is process optimization, as strains must be engineered for precursor supply, methyl and sulfur metabolism, and enzyme balance, while fermentation conditions, scale-up, and downstream recovery must also be optimized to make production economically competitive (Liu & Luo, 2026; Yan et al., 2026).
EGT is not made by one universal pathway. Instead, the literature describes a bacterial aerobic route, a fungal streamlined route, and a newer anaerobic route, all of which share histidine-derived intermediates, sulfur incorporation, and methylation but differ in pathway length, enzyme organization, oxygen dependence, and sulfur or methyl-donor usage. These differences matter because they determine which pathway is best suited for heterologous reconstruction in a fermentation host. The bacterial aerobic pathway is the best-characterized industrial template. In Mycobacterium smegmatis, the egtABCDE cluster encodes five enzymes that sequentially methylate histidine, build a sulfur-containing intermediate, catalyze oxygen-dependent C—S bond formation, remove the gamma-glutamyl group, and complete EGT formation through C—S cleavage. This route provides a mechanistic framework for metabolic engineering, but its multi-enzyme architecture makes flux sensitive to imbalance among steps, and to the availability of S-adenosylmethionine (SAM), gamma-glutamyl cysteine, Fe(II), oxygen, and pyridoxal 5′-phosphate. On the other hand, the fungal pathway is simpler. For example, in Neurospora crassa and several edible fungi, Egt1 and Egt2 condense the core chemistry into a smaller number of enzymatic steps, with Egt1 combining methyltransferase and sulfoxide synthase functions and Egt2 carrying out final C—S lyase chemistry. This streamlined organization bypasses the gamma-glutamyl cysteine intermediate. Because of this compactness, fungal pathways are attractive for heterologous reconstruction in fermentation hosts (Yan et al., 2026; Zhang, Liu, et al., 2025; Zhang, Ning, et al., 2025). The core engineering goal in microbial fermentation is to make the host behave like a balanced cell factory, not just a pathway carrier (Liang et al., 2025; Liu & Luo, 2026; Zhang, Liu, et al., 2025; Zhang, Ning, et al., 2025). Layers of optimization include 1) Chassis selection: model organisms such as E. coli, S. cerevisiae, and Corynebacterium glutamicum are widely used because they have mature genetic toolkits and well-defined backgrounds. E. coli is the most studied host, while C. glutamicum is attractive due to amino acid production and stress resistance (Liu & Luo, 2026). 2) Pathway reconstruction: engineering can follow the prokaryotic route, the fungal route, or hybrid designs. A hybrid strategy in E. coli combines fungal and bacterial modules to improve intermediate conversion efficiency by 3.8-fold (Liu & Luo, 2026). 3) Precursor supply: EGT production depends on histidine, cysteine, methionine, and related central‑carbon precursors, so increasing pathway expression alone often fails unless intracellular precursor pools are expanded (Yan et al., 2026). Reported strategies include feedback-resistant HisG variants, overexpression of histidine operons, strengthening 5-phosphoribosyl 1-pyrophosphate supply, and reducing competing pathways. For sulfur metabolism, strategies include engineering cysteine biosynthesis and sulfur assimilation. For methyl supply, researchers have used MetJ deletion, MetK variants, SAM1/SAM2 overexpression, and methyl-cycle reconstruction with SAM2, SAH1, and BHMT to improve SAM regeneration (Liu & Luo, 2026; Yan et al., 2026). 4) Transport and secretion: product export is also important. One study showed that introducing the transporter gene mfsT1 increased the extracellular fraction of EGT from 18.7% to 44.9%, indicating that secretion can significantly improve process performance by reducing intracellular accumulation which can intensify stress and complicate recovery (Liang et al., 2025; Yan et al., 2026).
Optimizing fermentation involves multiple interconnected factors, including host selection, precursor supplementation, oxygen regulation, productivity, and maintaining process stability. A key consideration is the balance between feeding precursors and relying on the organism's internal supply. Traditional methods of fermentation frequently incorporate supplements like methionine and cysteine, which can enhance yields in laboratory settings but also increase raw material expenses and complicate scaling up. Additional challenges arise when scaling up, for example although high EGT titers have been achieved in laboratory bioreactors, larger industrial systems often encounter significant mass-transfer limitations. Oxygen management is particularly crucial since the bacterial EgtB step requires oxygen, hence a lack of dissolved oxygen can significantly hinder flux and reduce overall yield. Therefore, a fermentation pathway that performs well in smaller reactors may underperform at larger scales unless aeration, mixing, and cell density strategies are adjusted accordingly. Additionally, productivity is as important as titer and yield, as it impacts reactor efficiency and capital costs. The optimal fermentation process is not merely the one that generates the highest EGT concentration per liter, but rather the one that achieves this output quickly and consistently in an industrial setting (Liu & Luo, 2026; Yan et al., 2026; Zheng et al., 2026). Downstream recovery is a major cost driver in microbial EGT production. Food and nutraceutical applications require appropriate product purity and removal of process-related impurities. Cell disruption, centrifugation, filtration, chromatography, and crystallization are the key unit operations to be optimized as an integrated purification process. This is one reason microbial fermentation is not automatically superior to other routes, because even when fermentation is efficient, poor recovery can outweigh the economic advantage. Product secretion, strain choice, and broth composition therefore influence both upstream productivity and downstream cost (Liang et al., 2025; Liu & Luo, 2026; Zheng et al., 2026).
4. Applications of EGT in food
The antioxidant and metal-chelating properties discussed above provide the basis for the use of EGT in food preservation. By limiting oxidative reactions and associated pigment changes, EGT helps in maintaining the quality and shelf life of food products. Browning and discoloration of fresh food products represent a significant economic challenge in the food industry. Traditionally, synthetic additives have been used to control oxidative deterioration and enzymatic browning; however, increasing consumer demand for clean-label products has evoked interest in natural alternatives. Consequently, there is growing demand for safe and natural compounds capable of preserving food quality. EGT has been reported to inhibit oxidative discoloration in food systems by reducing lipid oxidation and pigment degradation, such as myoglobin oxidation in meat products and astaxanthin (carotenoid pigment) oxidation in seafood. In addition, EGT was reported to reduce melanosis and enzymatic browning through inhibition of polyphenol oxidase (PPO) activity (Kitsanayanyong & Ohshima, 2022; Zhang, Liu, et al., 2025; Zhang, Ning, et al., 2025). Other applications of EGT in animal breeding and agricultural innovation (Abdalkarim Salih et al., 2021; Koshiyama et al., 2024; Orzołek et al., 2025; Yildiz et al., 2015) are included in supplementary text (S1).
This section outlines the various applications of EGT-rich extracts in different food categories (Table 3). Some studies compared the use of commercial L-ergothioneine with natural EGT-rich extracts, while others investigated post-harvest treatments such as immersion or spraying.
Table 3.
Applications of ergothioneine-rich extracts in food products.
| Food Category | Ergothioneine Source | Application | Investigations | Key Benefit / Outcome | Reference |
|---|---|---|---|---|---|
| Kuruma Shrimp | F. velutipes mushroom hot water extract | 25% (w/v) of the extract final concentration in the wet feed, 0.1 mL administered orally once daily for 1 week |
|
|
(Encarnacion et al., 2010) |
| Black Tiger & Pacific White Shrimps | F. velutipes mushroom extract | Immersion in 0.5% (w/v) mushroom extract at a ratio of 2:1 v/w shrimps for 1 h |
|
|
(Encarnacion et al., 2012) |
| Red Queen Crab | F. velutipes mushroom extract | Immersion in 1% mushroom extract at a ratio of 6:1 (v/w of crab) for 2 h |
|
|
(Encarnacion et al., 2011) |
| Minced Bigeye Tuna & Beef | F. velutipes mushroom dry powder extract and L-ergothioneine solution | 5 mL of mushroom extract or L-ergothioneine solution, both containing about 3 mg/mL EGT, was applied to 100 g of minced beef and bigeye tuna meat |
|
|
(Bao et al., 2008) |
| Minced Bigeye Tuna | F. velutipes mushroom dry powder extract | 5 mL mushroom extract per 100 g minced bigeye tuna meat |
|
|
(Bao et al., 2009) |
| Catfish fillet | F. velutipes mushroom hot water extract | 10 g of the extract per 100 g of feed twice daily for 4 weeks |
|
|
(Ha et al., 2021) |
| Salmon fillet (Coho salmon) | Pleurotus cornucopiae mushroom extract | 5 g of the extract per 100 g of feed twice daily for 2 months |
|
|
(Pahila et al., 2017) |
| Salmon fillet (Rainbow trout) | F. velutipes mushroom dry powder extract | 5 g of the F. velutipes mushroom extract per 100 g of minced salmon muscles |
|
|
(Pahila et al., 2017) |
| Emulsified Sausage | F. velutipes mushroom extract | 0.8% of mushroom extract |
|
|
(Tao et al., 2021) |
| Germinated Brown Rice Flour | Enoki mushroom extract | 3 g of the extract per 100 g of the rice |
|
|
(Truc et al., 2021) |
| Germinated Brown Rice | EGT extract from Aspergillus oryzae fungi | 4% of EGT concentrated extract in soaking water for 6 h |
|
|
(Ha et al., 2022) |
| White Button Mushroom | EGT powder | 0.12 mmol/L EGT spray |
|
|
(Qian et al., 2021) |
| Fresh-Cut Potato Slices | EGT powder | Immersion in 10 mg/mL EGT solution |
|
|
(Gu et al., 2025) |
| Arugula Baby Leaves | EGT powder | Leaves were dipped in 100 μM EGT concentration for 30 min |
|
|
(Sivakumar & Bozzo, 2024) |
| Fresh Broccoli | EGT powder | 24-h partial submersion of broccoli stalk in 20 μM EGT solution |
|
|
(Yan & Bozzo, 2026) |
| Litchi Fruit | EGT powder | 10-min immersion in 50 mg/L EGT solution |
|
|
(He et al., 2026) |
2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay, adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenosine triphosphate (ATP), ascorbate peroxidase (APX), butylated hydroxyanisole (BHA), catalase (CAT), dehydroascorbic acid (DHA), dehydroascorbate reductase (DHAR), 2,2-Diphenyl-1-picrylhydrazyl (DPPH), Total color difference (∆E), free fatty acids (FFA), ferric reducing antioxidant power (FRAP) assay, γ-aminobutyric acid (GABA), glutathione reductase (GR), glutathione peroxidase (GPX), glutathione (GSH), glutathione disulfide (GSSG), Hydrogen peroxide (H₂O₂), hydroperoxides (HPO), laccase (LAC), malondialdehyde (MDA), metmyoglobin (MetMb), peroxidase (POD), phenylalanine ammonia lyase (PAL), phenoloxidase (PO), polyphenol Oxidase (PPO), polyunsaturated fatty acids (PUFA), reactive oxygen species (ROS), ribonucleic acid (RNA), superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS), total hemocyte count (THC), total reducing power (TRP), Trolox equivalent antioxidant capacity (TEAC).
4.1. Meat-based products
EGT has recently attracted increasing interest for post-mortem preservation of fish and seafood products, primarily due to its antioxidant and anti-melanosis (anti-browning) properties. Edible mushroom extracts, particularly from Flammulina velutipes fruiting bodies and agricultural by-products such as SMS and spent mushroom compost (SMC), represent promising sources of natural antioxidant preservatives. Trimming waste from F. velutipes production has also been investigated as a source of EGT for preservation and color stabilization applications, particularly in the seafood industry (Bao et al., 2010). In crustaceans, EGT-rich mushroom extracts have been incorporated into feed before harvest or applied through immersion to reduce post-mortem melanosis and lipid oxidation. Studies in Kuruma shrimp, black tiger shrimp, Pacific white shrimp and Red Queen crabs collectively suggest that these approaches can limit melanosis during ice storage. Proposed mechanisms include inhibition of phenoloxidase activity, potentially through interactions with the copper center of the enzyme, and modulation of the prophenoloxidase activation cascade, alongside changes in the prophenoloxidase (proPO) gene expression (Encarnacion, Fagutao, Hirono, Ushio and Ohshima, 2010, Encarnacion, Fagutao, Shozen, Hirono and Ohshima, 2011; Encarnacion et al., 2012). Comparisons with L-ergothioneine suggest that EGT contributes to the anti-melanosis activity of mushroom extracts. However, L-ergothioneine showed stronger inhibition in one study, and similar effects in another, suggesting that EGT concentration and other extract components may influence their effects. Mushroom extracts also showed comparable inhibitory effects to synthetic melanosis inhibitors under the tested conditions (Encarnacion, Fagutao, Hirono, Ushio and Ohshima, 2010, Encarnacion, Fagutao, Shozen, Hirono and Ohshima, 2011, Encarnacion et al., 2012).
Owing to its antioxidant properties and ability to limit lipid and myoglobin oxidation, EGT has also been investigated for preservation and color stabilization of beef and bigeye tuna (Thunnus obesus). Studies using Flammulina velutipes mushroom extracts demonstrated improved color stability upon storage, attributed to protection against myoglobin and lipid oxidation and reduced metmyoglobin formation. Proposed mechanisms include scavenging reactive radicals and reducing highly oxidizing ferryl intermediates. However, the mushroom extract exhibited greater antioxidant effects than L-ergothioneine at equivalent EGT concentration in one comparison, suggesting activity contributed by other extract components. These findings indicate that the antioxidant effects of mushroom extract do not arise solely from EGT (Bao, Ushio and Ohshima, 2008, Bao, Ushio and Ohshima, 2009).
In addition, dietary supplementation of mushroom extracts was shown to improve the post-harvest quality of catfish (Pangasius hypophthalmus) fillets. Pre-harvest supplementation resulted in EGT accumulation in muscle tissue, with improved color stability, reduced lipid oxidation, and firmer texture during frozen storage (Ha et al., 2021). In salmonids, addition of Flammulina velutipes and dietary supplementation of Pleurotus cornucopiae extracts to minced rainbow trout (Oncorhynchus mykiss) muscle and coho salmon (Oncorhynchus kisutch) respectively reduced lipid hydroperoxide formation and preserved astaxanthin levels. The extent of protection varied with storage conditions, indicating that temperature management must be taken into consideration with antioxidant treatments (Pahila et al., 2017). Experiments using astaxanthin-loaded lecithin-based liposomes as or cell model further supported the relationship between lipid oxidation and astaxanthin degradation, while also highlighting possible contribution of other antioxidant compounds present in the mushroom extract, suggesting potential applicability in industrial food preservation systems (Pahila et al., 2019). Applications also extend to processed meat products. In emulsified sausage, Flammulina velutipes mushroom extract reduced lipid and protein oxidation, and showed comparable antioxidant activity to butylated hydroxyanisole (BHA), with improved sensory attributes and flavour of the sausages compared with the BHA-treated samples (Tao et al., 2021). For the catfish and sausage studies, findings concern whole mushroom extracts and do not establish the independent contribution of EGT.
Together, these studies indicate that mushroom extracts may help preserve meat quality by controlling lipid oxidation, pigment degradation, and melanosis, depending on the food matrix, extract composition, application method, and storage conditions. A research trend across these studies is the exploration of both dietary supplementation of extracts before harvest and direct treatment after harvest. Comparisons with purified EGT and other relevant controls remain important to distinguish the contribution of EGT from other mushroom extract components. Key experimental parameters and findings are summarized in Table 3.
4.2. Plant-based products
The existing literature contains relatively few examples of EGT use in preserving plant-based food products, using different treatment methods, and assessing different aspects of food quality including lipid oxidation, browning and chlorophyll retention. Studies in cereals, fresh produce and edible mushrooms suggest promising potential applications in controlling lipid oxidation, enzymatic browning, and post-harvest senescence.
In germinated brown rice and its flour, the inclusion of EGT-rich mushroom extracts during processing was shown to improve oxidative stability and preserve bioactive compounds. Treating rice with an EGT-rich Aspergillus oryzae extract during soaking increased γ-aminobutyric acid and γ-oryzanol contents, reflecting the protection of the bran layer and stabilization of germination-related metabolic processes (Ha et al., 2022), while inclusion of EGT-rich mushroom extract before flour production reduced lipid oxidation during storage. Higher extract concentrations showed similar effects in terms of oxidative stabilization but reduced sensory acceptability, highlighting the need to balance oxidative protection with product quality (Truc et al., 2021). These effects cannot be attributed solely to EGT because the extracts contain other components.
Control of enzymatic browning is another recurring application. In white button mushroom (Agaricus bisporus) and fresh-cut potato slices, EGT treatment reduced the activities of browning-related enzymes and helped maintain tissue quality during refrigerated storage (Gu et al., 2025; Qian et al., 2021). These effects were attributed to regulation of browning-related activities, maintenance of antioxidant defenses and membrane integrity. The changes in enzyme-associated gene expression and retention of endogenous ascorbic acid in white button mushrooms further suggest that the effect of EGT goes beyond direct antioxidant activity (Qian et al., 2021).
In green leafy vegetables, preservation mainly focuses on delayed senescence and prevention of chlorophyll loss during storage. EGT treatment helped maintain post-harvest quality in baby arugula leaves (Diplotaxis tenuifolia) under optimal storage conditions by reducing wilting and browning, preserving green color, and influencing endogenous antioxidant enzyme activity (Sivakumar & Bozzo, 2024). In fresh broccoli (Brassica oleracea var. italica), post-harvest treatment with EGT maintained product quality by reducing chlorophyll degradation and hydrogen peroxide levels through influencing the ascorbate–glutathione recycling pathway (Yan & Bozzo, 2026).
Recent work in litchi (Litchi chinensis Sonn.) extends EGT benefits to fruit pericarp browning. Immersion of the fruits in EGT solution was shown to slow senescence through coordinated multi-level regulation, including maintenance of antioxidant enzymatic activity and membrane integrity, preservation of non-enzymatic antioxidants, and suppression of browning-related enzymes (He et al., 2026).
Overall, a research trend in plant-based foods is the investigation of gene expression and energy metabolism in addition to measurements of browning and oxidation. However, to generalize these findings, experiments need to examine several experimental conditions including treatment concentrations, temperature dependence, as well as assess sensory acceptability. Table 3 summarizes the key parameters and outcomes of the studies discussed.
5. Applications of EGT in cosmetics
EGT has been reported to exert several beneficial effects on skin health, including support of skin barrier function, protection against oxidative stress associated with skin aging, anti-inflammatory activity, and mitigation of UV-induced damage. It may also influence melanogenesis and contribute to improved skin hydration. These effects are largely attributed to its antioxidant properties and its ability to modulate cellular redox balance. Evidence supporting these functions has been obtained from in vitro, in vivo, and ex vivo studies on human skin, with emerging but still limited data from clinical investigations (Zhou et al., 2026). Liu et al. reported the safety and potential benefits of EGT as a functional ingredient in cosmetic formulations, skincare products, and oral nutricosmetics. Owing to its antioxidant and cytoprotective properties, EGT is increasingly incorporated into cosmetic and cosmeceutical products, including anti-aging formulations, skin-protection products, and sunscreens. This growing industrial interest highlights the increasing demand for sustainable and cost-effective production sources of EGT (Liu, Tang, Wang, Jiang, Zhang, & Wang, 2023).
Clinical investigations, including randomized, double-blind trials and open-label pilot studies have reported improvements in selected skin parameters following oral supplementation with EGT or EGT-containing preparations. Oral supplementation of EGT or EGT preparations was shown to effectively reduce melanin, diminish the appearance of visible and brown spots, and significantly decrease wrinkle areas while improving skin glossiness and hydration (Cheng et al., 2022; Hanayama et al., 2024; Hanna et al., 2025; Zhang & Li, 2023). For topical use, EGT was tested in combination with other antioxidants or functional components for topical skin administration, such as vitamin C, vitamin E, ferulic acid, naringin, and botanical extracts across a range of clinical trial designs, including randomized, double-blind, split-face, and open-label studies, demonstrating significant reductions in fine lines and wrinkle depth, improved skin elasticity and hydration, enhanced skin brightness and tone evenness, decreased erythema, and accelerated recovery of damaged or irradiated skin barrier function (Amini-Nik et al., 2026; Draelos & Diaz, 2023; Sikora et al., 2021; Tao et al., 2025; Ye et al., 2025; Zhang, Liu, et al., 2025; Zhang, Ning, et al., 2025). However, since these findings concern multicomponent systems, they do not establish the independent contribution of EGT. When EGT was investigated as a single active topical agent (0.1%) in a 4-week clinical trial involving 31 healthy human subjects (aged 19–60) investigating UVA-induced skin hyperpigmentation (melanosis) on the back, results demonstrated significant suppression for melanin production (Liu, Tang, Wang, Jiang, Zhang, Liu, & Wang, 2023).
6. Translational constraints of EGT
Although EGT has demonstrated numerous health benefits and has been incorporated into food and other industrial applications, translating these benefits into controlled and targeted delivery remains challenging due to physicochemical and biological limitations, thereby motivating the development of advanced delivery technologies (Fig. 4). EGT possesses a strong biological rationale but has experienced relatively slow pharmaceutical translation. EGT has a molecular weight of 229.30 g/mol and low lipophilicity (logP ≈ 0–0.3). EGT is chemically stable across a wide pH range and resists autoxidation, with thermal decomposition occurring around 262–265 °C. However, it can interact with certain transition metal ions, such as Cu2+ and Fe2+, which may influence formulation stability under specific conditions (Wang et al., 2026). EGT is highly water-soluble and forms extensive hydrogen bonding and electrostatic interactions with surrounding water molecules, generating a strong hydration shell. Together with its zwitterionic nature, these properties limit passive diffusion across biological membranes. In addition, its high polarity can reduce compatibility with lipophilic solvents or carriers, presenting challenges for formulation development (Li, Wang, et al., 2025; Yadan, 2022). Furthermore, this high polarity and zwitterionic nature impede its effective crossing of biological membranes by passive diffusion. Instead, its cellular uptake is primarily mediated by OCTN1, also known as the ergothioneine transporter (ETT), encoded by the SLC22A4 gene. EGT exhibits high transport efficiency through OCTN1, with reported kinetic parameters including a Km of approximately 20 μM, indicating high affinity for the transporter. The SLC22A4 gene encodes OCTN1, which is widely conserved among vertebrates. Consequently, EGT accumulates preferentially in tissues expressing OCTN1. High concentrations have been reported in erythrocytes, liver, kidney, small intestine, bone marrow, and immune cells, as well as in several regions of the brain. Although OCTN1 is the principal transporter for EGT, genetic variation in SLC22A4 can affect transporter function, and consequently EGT uptake and tissue distribution. These findings suggest that genotype may contribute to interindividual variations in EGT handling, but at present there is insufficient evidence to recommend genotype-guided EGT supplementation. Future studies should determine whether SLC22A4 genotype predicts EGT exposure, tissue distribution, clinical response, optimum dose, or safety profile (Abdi Syahputra et al., 2025; Cheah & Halliwell, 2021; Gründemann, 2012; Gründemann et al., 2005, Gründemann, Hartmann and Flögel, 2022; Guo et al., 2026; Tang et al., 2018; Vo et al., 2022; Weigand-Heller et al., 2012; Wijesekara & Xu, 2024).
Fig. 4.
Translational challenges of EGT.
OCTN1-mediated transport plays a central role in the absorption, distribution, metabolism, and excretion (ADME) of EGT, resulting in a pharmacokinetic profile that differs from many conventional small-molecule compounds. Oral absorption depends strongly on OCTN1 in the small intestine, as OCTN1 knockout mice show markedly reduced intestinal exposure and systemic availability of ergothioneine, while the compound's hydrophilic, membrane-impermeable nature makes transporter-mediated uptake essential. Distribution is likewise transporter-driven rather than diffusion-driven, with EGT accumulating preferentially in liver, whole blood, kidney, spleen, lung, intestine, eye, and brain after oral dosing in mice, and tissue depletion in OCTN1 knockout animals indicates that alternative uptake pathways are limited in vivo. Consequently, plasma levels may not directly reflect tissue concentrations or biological activity. Uptake of EGT is saturable due to the transporter-mediated mechanism, which can lead to plateauing of intracellular levels at higher doses. In circulation, EGT exists largely in the erythrocytes, with only a fraction freely available in the plasma. Available animal data indicate that EGT is retained largely as the parent compound alongside only a small number of putative metabolites such as hercynine, S-methyl-ergothioneine, and ET-sulfonate. EGT exhibits relatively low systemic clearance, partly due to renal reabsorption mediated by OCTN1, and shows prolonged tissue retention, particularly in erythrocytes and metabolically active organs such as the liver and kidney. Rodent studies have reported tissue half-lives extending to several weeks (Borodina et al., 2020; Cheah & Halliwell, 2021; Gründemann, 2012; Gründemann et al., 2005; Kato et al., 2010; Meng et al., 2025; Tang et al., 2018; Wijesekara & Xu, 2024). Another important characteristic of EGT is its proposed role as a redox-responsive or “adaptive” antioxidant. Consequently, increasing the administered dose or intracellular availability does not necessarily translate into proportional increases in biological activity.
In addition, production of high-purity EGT remains relatively costly, contributing to its high market price. EGT can be obtained through extraction from natural sources or through chemical or biotechnological synthesis. Each production route involves distinct variables that influence the standardization and consistency of product quality. These variables include differences in raw material sources, matrix complexity, extraction or synthesis yields, and processing parameters (Harasym et al., 2025; Zhang, Liu, et al., 2025; Zhang, Ning, et al., 2025).
A bibliometric analysis published in 2025 highlighted several limitations in the current research landscape on EGT, including the scarcity of well-designed human clinical trials, lack of standardized dosing regimens, limited pharmacokinetic characterization, and the absence of validated clinical endpoints and biomarkers. The analysis also emphasized the gap between promising preclinical findings and available clinical evidence, as well as the incomplete mechanistic understanding of EGT's biological effects (Fu et al., 2025). These challenges contribute to difficulties in classifying EGT as a therapeutic agent and hinder its progress toward regulatory approval as a pharmaceutical drug. For pharmaceutical development, the principal bottlenecks are dependence on OCTN-1 mediated and saturable uptake, limited passive membrane permeability, interindividual variability in transporter function, formulation constraints, and the lack of standardized human pharmacokinetic, dose-ranging, and long-term safety data.
These challenges highlight the need for innovative strategies to better understand and modulate the pharmacokinetics of EGT, thereby facilitating its effective application through advanced delivery technologies.
7. Nano-delivery systems and formulation strategies for EGT
Recent research has increasingly explored advanced formulation strategies to improve the delivery of EGT in food, cosmetic, and therapeutic applications. Nano-delivery systems have emerged as promising platforms for overcoming the physicochemical and biological limitations associated with EGT, particularly its high polarity, limited membrane permeability, and transporter-dependent uptake. By encapsulating EGT within nanoscale carriers, these systems can enhance its specific stability, improve bioavailability, and enable controlled release, thereby optimizing its functional performance. Moreover, many nanocarriers used in food and biomedical applications are derived from biocompatible, biodegradable, and food-grade materials. Consequently, nano-encapsulation strategies have been widely investigated for the development of functional foods, natural preservatives, cosmeceutical formulations, and therapeutic delivery systems (Harasym et al., 2025; Wen, Tang, et al., 2025).
An in vivo pharmacokinetic study further highlighted the potential of nano-delivery systems to improve the pharmacokinetic profile of EGT. In this study, a self-emulsifying oral nanoemulsion formulation increased the absorption rate of EGT without altering the overall systemic exposure. Compared with conventional oral powder formulations, the nanoemulsion produced a 3.7-fold higher peak plasma concentration (Cmax) and a shorter time to reach maximum concentration (Tmax), indicating more rapid systemic availability. These findings suggest that nano-delivery strategies may enhance the absorption kinetics of EGT, however, because overall systemic exposure was not increased, they do not demonstrate improved extent of bioavailability or clinical efficacy (Jake Wang et al., 2025). In this section, we demonstrate recent examples of EGT formulations and encapsulation into nano delivery systems. Table 4 provides a comparative summary of the major EGT nanocarrier systems, including particle size, encapsulation efficiency or EGT loading, and key delivery findings.
Table 4.
Comparative summary of EGT nanocarrier systems and key delivery findings.
| System | Application | PS (nm) | ZP (mV) | EGT loading or EE (%) | Key Findings | Reference |
|---|---|---|---|---|---|---|
| Chitosan nanoparticles | Food preservation | 139.6 | – | 159.5 ± 3.4 μg/mg |
|
(Bao & Bach, 2025) |
| Liposomes | Food preservation | 150.3 ± 33.77 | - 44.1 ± 5.57 | 77.6% |
|
(Fan et al., 2026) |
| Hyaluronic acid-modified liposomes | Skin-specific | 92.8 ± 0.7 | −24.09 ± 0.38 | 76.6% ± 1.2 |
|
(Wang et al., 2026) |
| Liposomes | Skin-specific | 35.7 ± 2.9 | – | 88.6% |
|
(Li et al., 2026) |
| Hyaluronic acid-coated niosomes | Skin-specific | 176 | 14.0 | > 90% |
|
(Li, Guo, et al., 2025) |
| AGPMC nanovesicles | Skin-specific | 140.10 ± 3.33 | 29.7 ± 4.2 | 23.28% ± 0.53 |
|
(Chen, Long, et al., 2025) |
| Lignin nanoparticles | Pharmaceutical | 121.3 to 197.8 | −22.2 to −28.9 | 46.8% to 88.9% |
|
(Sharaf et al., 2025) |
| Virus-biomimetic melanin nanoparticles | Pharmaceutical | 172.8 ± 2.5 | −1.1 ± 0.0 | 2.1 to 3.2% (w/w) |
|
(Renfang-Zhu et al., 2026) |
AG86-β-glucan-poly(methionine-b-carboxybetaine) (AGPMC), Entrapment efficacy (EE), melanin nanoparticles (MNPs), metmyoglobin (metMb), nanoparticles (NPs), particle size (PS), zeta potential (ZP).
7.1. Food industry applications
In food packaging technology, advanced formulations provide promising opportunities to utilize the antioxidant properties of EGT. Jiang et al. developed an EGT-loaded lactoferrin/sodium alginate edible film intended for active food packaging applications. Incorporation of 70 μg mL−1 EGT into the film matrix significantly enhanced the antioxidant activity of the material and improved its UV-shielding properties. The formulation also showed antimicrobial performance against foodborne pathogens such as Escherichia coli and Staphylococcus aureus, as well as spoilage bacteria including Hafnia alvei and Acinetobacter spp. However, this activity was primarily associated with lactoferrin, particularly at higher lactoferrin concentrations (0.45%–0.6%). EGT appeared to have only a slight and lactoferrin-concentration dependent contribution to antimicrobial activity, possibly through metal-ion chelation, therefore the observed antimicrobial effects cannot be attributed to EGT alone. In addition, EGT influenced the structural properties of the film, improving opacity and producing smoother and more uniform cross-sectional morphology. Overall, this system highlights the potential of lactoferrin/sodium alginate films containing EGT as functional materials for active food packaging (Jiang et al., 2025).
The combined use of polysaccharide coatings and EGT has also been investigated for seafood preservation. Cai et al. evaluated a gum arabic coating enriched with 0.2% EGT for maintaining the quality of red sea bream during refrigerated storage. The combined formulation was more effective than either gum arabic or EGT applied individually. During 16 days of storage at 4 ± 1 °C, the treated samples maintained total volatile basic nitrogen (TVB-N) levels below 25 mg 100 g−1, along with lower pH, thiobarbituric acid reactive substances (TBARS), and K-values compared with controls. These results indicate reduced protein degradation, inhibition of lipid oxidation, and improved freshness during storage. Microbiological analysis further demonstrated reduced growth of mesophilic bacteria, Pseudomonas, Enterobacteriaceae, lactic acid bacteria, and yeast. Sensory and texture evaluations confirmed that the coating maintained overall product quality throughout the storage period. In addition, the EGT–gum arabic coating preserved the natural color of the fish by delaying the development of undesirable grey–blue discoloration, likely associated with the antioxidant activity of EGT and the barrier properties of the polysaccharide coating (Cai, Wu, et al., 2014). Similarly, a 0.3% EGT–chitosan coating was developed as a preservative system to maintain the quality of Japanese sea bass during refrigerated storage. Coating maintained pH stability and reduced the accumulation of TVB-N, peroxide value, and biogenic amines compared with untreated samples. Microbiological analysis showed lower counts of Pseudomonas spp. and total mesophilic bacteria in the coated samples. In addition, the EGT–chitosan coating preserved sensory, textural, and color quality of the fish during storage. Overall, the coating extended the shelf life of Japanese sea bass to approximately 16 days at 4 ± 1 °C compared with about 8 days for the untreated control. The enhanced preservation efficacy is likely due to the synergistic combination of the antimicrobial barrier properties of chitosan and the antioxidant activity of EGT (Cai, Li, et al., 2014).
In addition, nanotechnology offers promising prospects for EGT (Fig. 5). EGT was incorporated into chitosan nanoparticles (mean particle size 139.6 nm) to enhance its efficacy as a natural preservative for yellowfin tuna (Thunnus albacares) muscle. The ferrous forms of myoglobin, deoxymyoglobin (deoxyMb) and oxymyoglobin (oxyMb) are responsible for the bright red color of tuna meat. During frozen storage, these forms are oxidized to ferric myoglobin, metmyoglobin (metMb), resulting in undesirable brown discoloration. Although frozen storage slows deterioration, it does not fully prevent lipid oxidation and subsequent myoglobin oxidation. Application of EGT-loaded chitosan nanoparticles at a concentration of 100 mg nanoparticles kg−1 fish reduced lipid oxidation after six months of frozen storage. The nanoformulation significantly reduced TBARS accumulation compared with free EGT and chitosan nanoparticles. In addition, the nanoformulation better preserved color quality, maintaining the redness index within grade A and metmyoglobin levels within grade B according to established tuna quality classifications. The enhanced preservation efficacy may be attributed to the combination of EGT and chitosan. Compared with nanoformulations containing vitamin E or plant polyphenols, this system combines EGT and chitosan but no side-by-side comparison was performed, therefore the relative efficacy over other antioxidant nanoformulations cannot yet be established (Bao & Bach, 2025).
Fig. 5.
Nanoparticulate delivery systems and their merits for EGT delivery. Created in Biorender, Aly, M. (2026) https://BioRender.com/agi0bb5.
Chitosan-coated EGT liposomes were reported as an effective anti-browning treatment for Lanzhou lily (Lilium davidii var. unicolor) bulbs by inhibiting PPO and peroxidase activity, with sustained release of EGT during 12 days of storage, thereby delaying browning, reducing water loss, and limiting nutrient degradation (Fan et al., 2026).
Moreover, Chen et al. investigated sustained delivery of EGT using fava bean protein nanofibers as a food-grade carrier system. Fibrillation of fava bean 11S protein followed by crosslinking with Ca2+ and κ-carrageenan resulted in the formation of a gel matrix capable of enabling sustained release of EGT (10 mg/mL) during 6 h of in vitro simulated gastrointestinal digestion. This system demonstrates the potential of plant protein nanofibers as sustainable and edible carriers for bioactive compounds and suggests that fava bean protein matrices may serve as alternatives to animal-derived delivery systems (Chen, Zhou, et al., 2025).
Tian et al. also developed lactoferrin-chitosan hydrogel to improve EGT delivery for individuals with dysphagia. The optimal formulation displayed 78.33% loading efficiency for EGT with reduced early gastric release and enhanced intestinal release, supporting its potential as a food-grade sustained delivery system for EGT (Tian et al., 2026).
7.2. Skin-specific applications
EGT, together with other bioactive compounds, has also been incorporated into liquid crystal–based emulsion systems for cosmetic applications. This formulation approach highlights the advantages of liquid crystal emulsions compared with conventional emulsions in improving the stability and performance of cosmetic and cosmeceutical preparations. In one study, an ultra-micro liquid crystal (UMLC) emulsion was prepared using a simple emulsification method in which the size of the liquid crystal structures was controlled by adjusting the concentration of glyceryl stearate citrate. The resulting UMLC emulsion exhibited an average particle size of approximately 4.12 μm and demonstrated stability under light and temperature stress conditions during one month of storage at −10, 5, 45, and 50 °C. Compared with larger liquid crystal emulsions and conventional emulsions, the UMLC system showed higher viscosity and improved skin hydration and barrier properties. In addition, it enhanced dermal penetration of EGT, achieving permeation levels of 1.28% compared with 0.36% and 0.11% for the other formulations (Hua et al., 2024). A possible rationale for EGT delivery is that the hydrated lamellar domains can accommodate the polar zwitterionic active while the emulsion improves contact with the skin and modifies the local hydration environment, however this mechanism is a formulation hypothesis, and does not establish preferential benefit of EGT over other hydrophilic compounds.
In another study, EGT emulgels were developed to improve topical delivery and skin penetration. All formulations were non-irritant and skin compatible, with the optimal formulation containing liquid paraffin/Carbopol 934 showed the best performance, high spreadability, 48.48% antimicrobial inhibition, and 93.11% release for EGT over six hours (Gohil et al., 2026). To prevent or reduce radiation-induced skin injury, EGT‑sodium hyaluronate (EGT-NaHA) skin dressing was developed, with EGT as the main protective ingredient. In mice, the EGT-NaHA group displayed the lowest skin injury score, with delayed onset of erythema and desquamation, and regeneration of complete epidermis by day 24. The dressing also released about 50% of EGT by 3 h and reached 90% cumulative release over time, supporting its use as a local skin delivery system (Tian et al., 2024).
EGT was also reported to improve chitosan/hyaluronan wound dressings by protecting hyaluronan from oxidative damage, and accelerating healing. In rabbit ischemic wounds, EGT-functionalized membranes outperformed both unfunctionalized membranes and untreated controls, via enhanced tissue regeneration and faster wound closure, underscoring its promise as a cytoprotective antioxidant for advanced wound care applications (Valachova et al., 2021). In another study involving hyaluronic acid-based wound dressing, EGT also acted as an antioxidant stabilizing excipient, limiting oxidative depolymerization and preserving hyaluronic acid's molecular weight, structure, viscosity and water retention capacity, without compromising hyaluronic acid's mediated cell migration, thereby supporting its use to maintain the functionality and durability of hyaluronic acid-based dressings (Ma et al., 2026).
EGT-modified eggshell membrane dressing was also designed to respond to the acidic/oxidative environment of diabetic wounds by releasing EGT to boost antioxidant protection, reduce cell damage and apoptosis, improve lubrication, and shift macrophages toward a more healing-promoting phenotype. Together, these effects accelerated diabetic wound repair, achieving about 87% closure by day 14 (Yu et al., 2026). Another study co-loaded EGT with dipotassium glycyrrhizate in a temperature responsive made of hydrogel gelatin/sorbitol/tremella polysaccharide for diabetic wounds, releasing EGT faster under acidic wound-like conditions and achieving combined antioxidant actions from EGT and dipotassium glycyrrhizate. In diabetic mice, it achieved 96.62% wound closure by day 12 while improving blood flow, angiogenesis, inflammation control, collagen formation and tissue remodeling, further supporting EGT's value in smart, multifunctional diabetic wound dressings (Chen et al., 2026).
Lipid-based nanovesicles have also been explored as nanocarriers for the delivery of EGT in cosmeceutical formulations. Wang et al. developed an adjuvant treatment for acne consisting of paeonol, totarol, and EGT encapsulated in hyaluronic acid–modified nanoliposomes (PTE-NLPs) to overcome limitations related to solubility, stability, and skin penetration. The resulting nanoliposomes exhibited a uniform spherical morphology with a particle size of 92.8 ± 0.7 nm and a zeta potential of +24.09 ± 0.38 mV, demonstrating good storage stability for 30 days at 4 °C, room temperature, and 45 °C. EGT was incorporated at 1% (w/w) with an encapsulation efficiency of 76.6 ± 1.2%. The formulation exploited the compositional similarity between liposomal lipids and stratum corneum lipids, together with the presence of low-molecular-weight hyaluronic acid (3–10 kDa), resulting in enhanced skin penetration, improved hydration, and increased cellular uptake with enhanced follicular targeting compared with free PTE. Consequently, the system increased EGT skin permeation and retention by 225.92% after 24 h in Franz diffusion cell experiments. Both in vitro and in vivo studies further demonstrated that PTE-NLPs exhibited improved safety, anti-inflammatory activity, and antibacterial effects against Cutibacterium acnes compared with the free components, highlighting the potential of nanotechnology-based delivery systems to overcome formulation and delivery challenges (Wang et al., 2026).
EGT was also reported promising for skin rejuvenation purposes. In a study by Li et al., 2026, EGT was co-loaded with coenzyme Q10 in topical nanoliposomal delivery system constructed using protopanaxatriol-type ginsenoside metabolites (PPTGM) as a cholesterol substitute, to improve transdermal delivery and protect against skin-aging-related mitochondrial dysfunction. The nanoliposomal system significantly enhances EGT's bioactivity and skin delivery by overcoming its native barrier limitations. The ultra-small (∼36 nm) unilamellar nanocarrier achieved an EGT encapsulation efficiency of up to 88.6% within its aqueous core, alongside co-encapsulated coenzyme Q10, enabling deep transdermal delivery of EGT into the viable epidermis and dermis, with a 16-fold increase in cumulative skin permeation compared to free EGT solution. It also enhanced stem cell migration and tissue repair, while protecting the mitochondria from oxidative stress by restoring membrane potential and suppressing mitochondrial superoxide accumulation, highlighting its potential for antiaging skincare applications (Li et al., 2026).
For protection against UV-induced skin damage, Li et al. developed EGT-loaded deformable hyaluronic acid–modified nanoniosomes for transdermal delivery. Encapsulation within hyaluronic acid-coated nanoniosomes was intended to improve cellular uptake and reduce reliance on OCTN1-mediated transport. Niosomes, which can exhibit greater deformability than conventional liposomes, facilitate penetration across the stratum corneum and delivery to deeper skin layers. The formulation consisted of a non-ionic surfactant (steareth-2), cholesterol, and a cationic lipid, while additional hyaluronic acid coating enhanced skin permeability and interaction with cellular receptors. The resulting nanocarrier showed a particle size of 176 nm, encapsulation efficiency of over 90%, and a zeta potential of +14.0 mV. The system maintained particle stability for 7 days and exhibited sustained release of EGT for up to 50 h. These properties enhanced the antioxidant, anti-inflammatory, and anti-photoaging effects of EGT against UV-induced skin damage. In vitro and in vivo studies demonstrated increased ROS scavenging, reduced mitochondrial dysfunction, decreased DNA and collagen damage, lower pro-inflammatory cytokine levels, and inhibition of apoptosis compared with free EGT and other formulations (Li, Guo, et al., 2025).
Another strategy to enhance transdermal delivery of EGT involved encapsulation within AG86-β-glucan-poly(methionine-b-carboxybetaine) (AGPMC) nanovesicles designed to target age-associated lipofuscin accumulation in skin cells. These smart nanovesicles contain an AG86 peptide moiety that promotes targeting of basal skin keratinocytes, while the polymeric structure enables ROS-responsive release of EGT in environments with elevated intracellular oxidative stress. AGPMC-targeted nanovesicles showed the strongest overall delivery performance compared with untargeted nanovesicles and free EGT, mainly by improving skin penetration, cellular uptake, and ROS-responsive behavior (Chen, Long, et al., 2025).
7.3. Pharmaceutical applications
The antioxidant and ROS scavenging properties of EGT have evoked increasing interest in its potential applications for radioprotection. An oral, bioadhesive EGT hyaluronate gel (EGT@HA) was designed to prolong the presence of EGT in the gastrointestinal tract for protection against radiation-induced gastroenteritis. The approach combined EGT's radioprotective antioxidant capabilities with the gastrointestinal retention properties of hyaluronic acid. Results indicated that EGT exhibited strong radical-scavenging activity, effectively reduced radiation-induced ROS, and minimized DNA damage, mitochondrial injury, and apoptosis in cells. In irradiated mice, the EGT@HA gel significantly decreased tissue damage, inflammation, and imbalance in gut microbiota, while demonstrating biosafety (Liu, Wang, Liu, Zhao, Ding, Zhang, et al., 2023).
For the targeted eradication of Helicobacter pylori (H. pylori), EGT was encapsulated in lignin nanoparticles prepared using an ultrasonic-assisted solvent precipitation/homogenization method and optimized by response surface methodology. Sharaf et al. incorporated EGT into lignin nanoparticles, producing spherical particles with an average size of 121.8 ± 0.57 nm, an encapsulation efficiency of 88.90%, and a zeta potential of −28.9 ± 0.6 mV. The formulation exhibited sustained release of EGT over 24 h, with maximum release under acidic conditions simulating gastric mucosa (pH 6.8). This pH-responsive behavior may be attributed to intermolecular interactions between EGT and the lignin matrix. Compared with free EGT, the nanoformulation showed higher antioxidant activity, likely due to improved dispersion and stability. In antimicrobial assays, EGT-loaded lignin nanoparticles exhibited enhanced activity against H. pylori, showing concentration- and time-dependent inhibition with 81.61% growth suppression after 48 h, with lower minimum inhibitory concentration than pure EGT and unloaded lignin NPs. These findings suggest that lignin-based nanocarriers may enhance the delivery and functional performance of EGT and highlight their potential for oral strategies targeting H. pylori infection (Sharaf et al., 2025).
Furthermore, EGT was used as a targeting moiety owing to its high affinity to OCTN1 receptor, which was proven useful in management of dry age-related macular degeneration (dAMD) by engineering virus-biomimetic melanin nanoparticles (VMNPs) surface-functionalized with EGT. This structural design enabled the nanoparticles to overcome ocular barriers, and enhance intraocular retention, cell transcytosis, and deep retinal penetration following simple eye-drop administration. Intracellularly, VMNPs were shown to escape lysosomes, scavenge total and mitochondrial ROS, and activate cytoprotective pathways by upregulating HMOX1 and SLC7A11 while suppressing NF-κB-mediated inflammation. In a rabbit model of dAMD, twice-daily topical application of VMNPs effectively prevented photoreceptor apoptosis and structural retinal degeneration, with comparable therapeutic efficacy to invasive intravitreal injections of Pegcetacoplan with excellent ocular safety (Renfang-Zhu et al., 2026).
8. Safety/regulatory considerations, future research trends and limitations
The increased interest in EGT as a functional ingredient in foods, cosmetics, and biomedical formulations necessitates careful evaluation of its safety profile and regulatory status. EGT is generally regarded as a low-toxicity antioxidant with a favorable safety profile, supported by its natural occurrence in foods and its selective accumulation in human tissues through OCTN1. Toxicological assessments have consistently shown low cytotoxicity and good biocompatibility in both in vitro and in vivo studies (Cheah & Halliwell, 2012; Schauss et al., 2011).
From a regulatory point of view, synthetic L-ergothioneine has been designated by EFSA as safe, and was approved as a novel food ingredient for use in food supplements and fortified foods at specified intake levels. In the United States, it has also been recognized as GRAS for use in conventional foods and dietary supplements, further supporting its commercialization as a functional ingredient. These regulatory approvals have facilitated the incorporation of EGT into a variety of food products and nutraceutical formulations, aiming at enhancing antioxidant capacity and supporting health promotion.
Despite the favorable regulatory status of EGT for food and supplement applications, its classification as a pharmaceutical agent remains challenging, owing to the limited number of well-designed human clinical trials and incomplete characterization of pharmacokinetic and pharmacodynamic profiles, thereby hindering its translation into an approved therapeutic drug. Moreover, differences in production methods such as extraction from natural sources, chemical synthesis, or microbial biosynthesis pose more challenges including variability in purity, yield, and formulation characteristics, emphasizing the need for standardized production and quality control protocols. Overall, current evidence supports the safety of EGT for dietary and cosmetic applications, however the main limitation is the lack of large, long-term human studies of EGT supplementation. Available human and animal data suggest that EGT is well-tolerated, with no treatment-related safety concerns in a one-year pilot human trial using 25 mg per capsule three times weekly, or in a 90-day rat study at doses up to 1600 mg/kg body weight per day. Nevertheless, the absence of robust multi-year safety data means that the long-term safety of high-dose EGT supplementation cannot yet be definitely confirmed (Marone et al., 2016; Yau et al., 2024; Zajac et al., 2025). Addressing these challenges will be essential for facilitating broader regulatory approval and expanding the translational potential of EGT-based formulations (Fig. 6).
Fig. 6.
Future research directions of EGT. Created in Biorender. Aly, M. (2026) https://BioRender.com/fcvpzzf.
Future research should prioritize several areas. For quantification of EGT in food, analytical standardization should define the sampled food fraction, dry or wet weight basis, extraction recovery, and storage stability. Validated chromatographic methods should report selectivity, calibration range, detection and quantification limits, precision and matrix effects. Free, encapsulated and total recoverable EGT should be distinguished where relevant. Regarding clinical trial design, studies should use chemically characterized preparations with placebo or other appropriate controls. Primary endpoints should be prespecified, and dose-ranging studies should measure baseline dietary exposure, plasma EGT levels, renal function, tissue retention, as well as adverse effects over an adequate follow-up period. In addition, development of nanoformulated ingredients should include full in vitro physicochemical characterization, in vivo performance, and safety assessment, together with appropriate product specifications and labelling under the relevant regulatory framework.
Finally, the present review is subject to limitations. Much of the available evidence on EGT is derived from in vitro, in vivo and food-model studies, while well-designed human clinical studies remain limited. Differences in EGT source, purity, dose, formulation, food matrix and outcome measures also limit direct comparison across studies and preclude formal meta-analysis. In addition, a substantial proportion of the food preservation literature concerns Asian food systems, particularly mushrooms, seafood and rice-based products, therefore the applicability of these findings to other dietary systems requires further investigation. As a narrative review, this article does not provide the systematic search, or quantitative synthesis procedures required for a systematic review or meta-analysis.
9. Conclusions
EGT is a promising antioxidant with potential applications in food preservation, functional foods, nutraceuticals, cosmetics and pharmaceutical formulations. Current evidence supports its capacity to limit oxidation, enzymatic browning, and pigment degradation, dependent on EGT source, purity, formulation, food matrix and experimental model. Results obtained with EGT-rich mushroom extracts should therefore be distinguished from those of purified EGT. Microbial fermentation and valorization of mushroom-processing by-products support the sustainable production of EGT, whereas delivery technologies may improve formulation stability and functional performance. Future work should prioritize standardized EGT quantification methods, well-designed clinical trials, direct comparisons of EGT preparations and delivery systems, and relevant safety and regulatory assessment to support reliable food and nutraceutical applications.
Generative artificial intelligence
During the preparation of this work, the author(s) used ChatGPT edu for grammatical correction. The author(s) reviewed and edited the output as needed and take full responsibility for the content of the published article.
CRediT authorship contribution statement
Salma H. Katary: Writing – original draft, Visualization, Investigation, Data curation. Maha Nasr: Writing – review & editing, Writing – original draft, Validation, Supervision, Conceptualization.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was funded by seed grant from College of Medicine and Health Sciences, United Arab Emirates University (grant number G00005655).
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.fochx.2026.104638.
Appendix A. Supplementary data
Supplementary S1: Applications of EGT in animal breeding and agricultural innovation.
Data availability
No primary research results, software or code have been included, and no new data were generated as part of this review.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary S1: Applications of EGT in animal breeding and agricultural innovation.
Data Availability Statement
No primary research results, software or code have been included, and no new data were generated as part of this review.