Ergothioneine: from biosynthesis to sustainable biomanufacturing and health applications.

Ergothioneine (ERG) is a naturally occurring sulfur-containing histidine derivative that has attracted considerable attention because of its exceptional chemical stability, tissue selective accumulation and potential health-promoting properties. Although humans cannot synthesize ERG de novo, it can be obtained from the diet and actively accumulated in multiple tissues through the specific transporter OCTN1, suggesting an important physiological role. In recent years, sustained advances in the study of ERG natural sources, biosynthetic pathways, microbial biomanufacturing, chemical synthesis and bioactivities have established ERG as a focal topic at the interface of natural products, biomanufacturing and nutritional health. This review summarizes the natural distribution and dietary sources of ERG, with particular emphasis on the differences among bacterial, fungal and anaerobic ERG biosynthetic pathways in pathway complexity, sulfur utilization, methyl donor supply and oxygen dependence, and discusses the implications of these natural routes for engineering design. We then outline the principal strategies used to construct microbial cell factories for ERG production, including pathway-source selection, precursor optimization, reinforcement of methyl and sulfur metabolism, transport engineering, fermentation process optimization and low-cost routes that do not depend on expensive precursor supplementation. We further distinguish mechanistic evidence from application-level evidence when evaluating the roles of ERG in antioxidation, anti-inflammation, healthy ageing, neuroprotection and the prevention of cardiovascular and metabolic disorders, and discuss its prospects in functional foods, dietary supplements and related health industries. Finally, we highlight the key challenges and future directions in large-scale manufacturing, mechanistic elucidation, clinical validation and product development. Overall, integrating natural biosynthesis, engineering performance, and evidence-based applications provides a framework for the rational development and industrial translation of ERG.