Multi‐Omics Reveals Impact of Hypoxia on Lactate Metabolic Switch and Monoclonal Antibody Production in CHO Fed‐Batch Cultivation

Oxygen supply is critical for mammalian cell culture. Insufficient oxygen supply or oxygen inhomogeneity in large-scale bioreactors often leads to attenuated process performance, such as reduced cell growth, viability, and productivity. However, the understanding of how hypoxia affects process performance by modulating the underlying biological mechanisms of Chinese hamster ovary (CHO) cells remains limited. In this study, a comprehensive multi-omics analysis was performed to investigate the impact of hypoxia on intracellular biology. Systematic analysis of the multi-omics data revealed that moderate hypoxia suppressed mitochondrial respiration function and respiratory electron transport, while enhancing the activity of the glycolytic pathway. The reactive oxygen species (ROS) were also elevated under hypoxia. Correlation analysis revealed that the specific lactate production rate during the late-stage culture correlated significantly with the activity of the biosynthesis pathways for oxidized polyunsaturated fatty acid (PUFA) derivatives and cholesterol. This finding suggests that optimizing the levels of these compounds in the media might improve lactate metabolism and antibody production.