Safe and Effective Antioxidant: The Biological Mechanism and Potential Pathways of Ergothioneine in the Skin

Abstract

Ergothioneine, a sulfur-containing micromolecular histidine derivative, has attracted increasing attention from scholars since it was confirmed in the human body. In the human body, ergothioneine is transported and accumulated specifically through OCTN-1, especially in the mitochondria and nucleus, suggesting that it can target damaged cells and tissues as an antioxidant. It shows excellent antioxidant, anti-inflammatory effects, and anti-aging properties, and inhibits melanin production. It is a mega antioxidant that may participate in the antioxidant network system and promote the reducing glutathione regeneration cycle. This review summarizes studies on the antioxidant effects of ergothioneine on various free radicals in vitro to date and systematically introduces its biological activities and potential mechanisms, mostly in dermatology. Additionally, the application of ergothioneine in cosmetics is briefly summarized. Lastly, we propose some problems that require solutions to understand the mechanism of action of ergothioneine. We believe that ergothioneine has good prospects in the food and cosmetics industries, and can thus meet some needs of the health and beauty industry.

Keywords: antioxidant; cosmetics; ergothioneine; inflammation; skin.

Figure 1

EGT metabolism in the cell: as an intracellular antioxidant, it may have a protective effect on oxidative damage and inflammation caused by exogenous factors reactive oxygen species (ROS) or UV. When cells are damaged or stressed, OCTN-1 transporters are expressed in large quantities to transport EGT across membranes to cells, and EGT can protect cells in different intracellular subcellular organelles in many ways. After entering the cells, EGT can rapidly chelate metal ions in the cytoplasm to prevent further damage to cells by the Fenton reaction. Simultaneously, EGT potentially regulates the activities of PARPs and sirtuin family enzymes and indirectly affects the transport and circulation of NAD+ in the cytoplasm and mitochondria, directly affecting ROS levels in mitochondria. In the nucleus, EGT protects the normal transcription of DNA and prevents deletions, especially DNA damage caused by copper ions. Additionally, EGT can inhibit the production of tumor necrosis factor-alpha (TNF-α), interleukin (IL)−1β, IL-6, and other inflammatory factors, thereby protecting the cells.

Figure 2

Mechanism of EGT and NAD+ cyclic pathway. In mitochondria, the consumption of NAD+ participates in the TCA cycle of cell energy metabolism and NADP+ production by NAD is influenced by NAD kinase, which further generates NADPH. NADPH can be used as the substrate of glutathione reductase (GR) to reduce GSSG to glutathione (GSH), which is necessary for the activities of the antioxidant enzymes glutathione peroxidase (GPx) and glutathione transferase (GST) and is one of the important ways to improve the antioxidant capacity of cells. EGT promotes this effect by regulating the action of NAD+ pools in mitochondria. Additionally, the antioxidant properties of EGT can directly remove excess ROS, upregulate the activity of GSH-px, and synergically participate in the antioxidant effect of cells.

Figure 3

Anti-inflammatory mechanism of EGT on AP-1 and MAPKs signaling pathway. Under the induction of environmental pressure, UV or oxidative damage, ROS can easily attack the nucleus and produce a large number of inflammatory cytokines, then activate the NF-κB cascade signaling pathways. Therefore, the nucleus began to express OCTN-1 in large quantities to promote more EGT transport into cells to play a role. While clearing ROS, EGT inhibited the production of activated AP-1 and MAPKs cascade signaling pathways to relieve inflammation.

Figure 4

EGT potentially regulates RUNX1 via the protective skin barrier. Additionally, EGT can potentially downregulate the inflammatory factor IL-33 induced by MAPK kinase, reduce the production of inflammatory markers (loricrin, keratin 1, and keratin 10), and indirectly regulate apoptosis caused by p53/63 by inhibiting the excessive increase in ROS. Interestingly, EGT and RUNX1 protein expression induce a strong binding energy related to the proliferation and differentiation of keratinocytes or skin stem cells, and ultimately promote the renewal of skin barrier function.

Figure 5

Prediction of EGT binding with related proteins by STITCH database cluster analysis.