Bio-based glutathione production: Microbial strategies and challenges

Glutathione, a bioactive tripeptide non-ribosomally synthesized by the cell, is a multifunctional compound showing broad applications in diverse fields. In recent years, the growing market demand has underscored the importance of improving glutathione production efficiency. Bio-based production, the primary industrial method for glutathione manufacturing, has thus become a focal point of research. In this review, centering on microbial fermentation, the main biotechnological approach for glutathione synthesis, we first outline its early historical development in which glutathione yield is enhanced through optimization of fermentation conditions. We then summarize the recent advances in constructing high-producing cell factories by evolutionary and metabolic engineering. Besides that, the supplementary methods for glutathione bioproduction, such as enzymatic conversion and whole-cell catalysis, are briefly illustrated, and challenges related to different production technologies are also presented. Finally, future perspectives towards the development of next-generation microbial platforms, especially Saccharomyces cerevisiae, the most widely used glutathione-producing species, for more efficient and sustainable fermentation-based production, are discussed.