{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T05:45:53Z","timestamp":1785735953105,"version":"3.56.0"},"reference-count":129,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>Chinese hamster ovary (CHO) cells serve as the predominant platform for producing recombinant therapeutic proteins in biopharmaceutical manufacturing, the production capacity of which relies heavily on efficient protein synthesis, folding, and secretion pathways. However, during high-density and prolonged cultivation, these cells frequently encounter bottlenecks\u2014including excessive lactate and ammonia accumulation, redox imbalance, and endoplasmic reticulum (ER) stress\u2014which ultimately constrain both the yield and quality of target protein. To overcome these limitations, metabolic engineering has emerged as a key strategy; through systematic modification of the CHO cellular metabolic network, it enhances recombinant protein yield, optimizes critical product qualities such as glycosylation, and improves overall process robustness. This review summarizes recent advances in CHO cell metabolic engineering, encompassing the regulation of central metabolic pathways, glycosylation engineering, cell cycle and metabolic reprogramming, culture condition optimization, byproduct accumulation control, and the application of systems biology and artificial intelligence technologies, including genome-scale metabolic modeling, machine learning-guided target prediction, and dynamic process control. These advances have significantly reduced biopharmaceutical production costs, improved scalability, and shortened time-to-market for monoclonal antibodies and other complex biologics. As the field transitions from single-gene manipulation toward multi-target, dynamic, and system-level rational design, metabolic engineering is advancing CHO cells into more efficient and intelligent \u201ccell factories\u201d, thereby providing sustained momentum for the industrial production of biologics.<\/jats:p>","DOI":"10.3389\/fbioe.2026.1847073","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T05:29:59Z","timestamp":1785734999000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Advancing recombinant protein production in CHO cells through metabolic engineering"],"prefix":"10.3389","volume":"14","author":[{"given":"Lu","family":"Hou","sequence":"first","affiliation":[{"name":"Institutes of Health Central Plains, Xinxiang Key Laboratory for Tumor Drug Screening and Targeted Therapy, Henan Medical University","place":["Xinxiang, China"]},{"name":"International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Li","sequence":"additional","affiliation":[{"name":"International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, Henan Medical University","place":["Xinxiang, China"]},{"name":"Henan Key Laboratory of Neurorestoratology and Protein Modification, The First Affiliated Hospital of Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Li","sequence":"additional","affiliation":[{"name":"Institutes of Health Central Plains, Xinxiang Key Laboratory for Tumor Drug Screening and Targeted Therapy, Henan Medical University","place":["Xinxiang, China"]},{"name":"International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaolei","family":"Geng","sequence":"additional","affiliation":[{"name":"International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, Henan Medical University","place":["Xinxiang, China"]},{"name":"Henan Key Laboratory of Neurorestoratology and Protein Modification, The First Affiliated Hospital of Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyun","family":"Wang","sequence":"additional","affiliation":[{"name":"International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, Henan Medical University","place":["Xinxiang, China"]},{"name":"Henan Key Laboratory of Neurorestoratology and Protein Modification, The First Affiliated Hospital of Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institutes of Health Central Plains, Xinxiang Key Laboratory for Tumor Drug Screening and Targeted Therapy, Henan Medical University","place":["Xinxiang, China"]},{"name":"International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, Henan Medical University","place":["Xinxiang, China"]},{"name":"Henan Key Laboratory of Neurorestoratology and Protein Modification, The First Affiliated Hospital of Henan Medical University","place":["Xinxiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.ymben.2011.07.002","article-title":"Metabolic flux analysis of CHO cells at growth and non-growth phases using isotopic tracers and mass spectrometry","volume":"13","author":"Ahn","year":"2011","journal-title":"Metab. 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