Regulating microbial cell factories to resist ROS stress in chemical production

Escherichia coli (E. coli) cell factories are widely used to convert biomass-derived substrates into bulk and fine chemicals, including amino acids and organic acids. During high-level chemical production, however, product accumulation and metabolic burden can impair cell viability, partly through the excessive generation of reactive oxygen species (ROS). ROS are unavoidable by-products of aerobic metabolism and can be buffered by basal antioxidant defence systems under physiological conditions. Once ROS accumulation exceeds cellular detoxification capacity, oxidative damage to proteins, lipids and DNA compromises growth, stress tolerance and product formation, thereby limiting further improvements in chemical yield. A mechanistic understanding of how ROS levels affect the productivity of E. coli cell factories is therefore essential for developing dynamic strategies to control oxidative stress and improve chemical biosynthesis. In this review, we focus primarily on ROS regulation in E. coli cell factories, while also discussing relevant mechanisms and engineering strategies in eukaryotic microbial systems where appropriate. We summarize the general principles of ROS homeostasis, including regulatory circuit architecture, functional components and design strategies. We further highlight recent advances, remaining challenges and potential solutions for engineering ROS-balanced microbial cell factories with improved robustness and production efficiency.