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Intracellular Lactate Modulation Alters Histone Modifications and CHO Cell Performance in Fed-Batch Culture
Mona Hoseini Soflaee1, Ricardo Romero-Moreno1, Bethany Cheng1
1Cell Culture and Fermentation Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA.
Biotechnology and Bioengineering
|April 15, 2026
Summary
Lactate reduction in the nucleus of Chinese hamster ovary (CHO) cells boosts protein production and cell viability. This finding suggests lactate is a regulatory metabolite, not just waste, impacting cell performance and epigenetics.
Area of Science:
- Biotechnology
- Cellular Metabolism
- Epigenetics
Background:
- Lactate, a byproduct of Chinese hamster ovary (CHO) cell metabolism, is traditionally viewed as waste.
- Emerging evidence suggests lactate may have regulatory roles in cellular functions.
Purpose of the Study:
- To investigate the impact of modulating intracellular lactate levels within specific cellular compartments on CHO cell performance.
- To explore the link between lactate metabolism, epigenetic modifications, and cellular health.
Main Methods:
- Engineered CHO cells to co-express lactate oxidase (LOX) and catalase (CAT) in cytosol, nucleus, or mitochondria.
- Assessed effects on viable cell density, protein titer, oxidative stress, and epigenetic markers (histone acetylation, lactylation).
Main Results:
- Reducing nuclear lactate significantly increased viable cell density (~40%) and protein titer (~35-40%) while decreasing oxidative stress.
- Mitochondrial lactate reduction had minimal impact, highlighting the importance of lactate's subcellular localization.
- Intracellular lactate reduction correlated with decreased histone acetylation and lactylation, reduced DNA damage markers, and improved genome stability.
Conclusions:
- Lactate acts as a regulatory metabolite influencing epigenetic state and cellular performance, beyond being a simple metabolic byproduct.
- Targeted reduction of intracellular lactate, particularly in the nucleus, is a promising strategy for enhancing CHO cell culture productivity and stability.
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