The increasing global prevalence of metabolic diseases, such as type 2 diabetes mellitus (T2DM), metabolic dysfunction-associated steatohepatitis, and atherosclerosis, is a significant public health concern. The alarming increase in rates of obesity, especially among children, exacerbates the severity of this issue. In 2019, the International Diabetes Federation reported that 463 million people had been diagnosed with diabetes. The federation predicts that by 2045, the number of people with diabetes will reach a 700 million [1].

Ergothioneine (EGT) is a natural betaine amino acid found in many foods, especially mushrooms. A derivative of histidine (2-mercaptohistidine trimethylbetaine), EGT was first isolated from the ergot fungus Claviceps purpurea in 1909, from which it derives its name. This compound has been reported to possess several beneficial properties, including antioxidant, anti-inflammatory, anti-apoptotic, anti-aging, and metal-chelating effects, thereby playing a cytoprotective role in vitro. Moreover, EGT has shown potential therapeutic effects in a range of diseases, including chronic inflammatory diseases, central nervous system diseases, cardiovascular diseases, liver diseases, kidney diseases, eye diseases, and cancer, among others [[2], [3], [4], [5], [6]].

However, the in vivo and clinical role of EGT in diseases related to metabolic disorders and its specific function remains unclear. Here, we review the structural basis, transport, metabolism, and physiological roles of EGT, and its potential applications in several metabolic disorder-related diseases, including glucose metabolism, lipid metabolism.