{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T15:51:20Z","timestamp":1789487480114,"version":"build-2803163510"},"reference-count":47,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:00:00Z","timestamp":1782604800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:00:00Z","timestamp":1782604800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech &amp; Bioengineering"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Chinese hamster ovary (CHO) cells are the leading host for recombinant therapeutic protein production in the biopharma industry. In this study, we investigated how feeding acidic forms of tricarboxylic acid (TCA) cycle intermediates\u2014malic acid, succinic acid, and \u03b1\u2010ketoglutaric acid\u2014affects cell culture performance and metabolism in two industrial IgG\u2010producing CHO cell lines. These intermediates were used as pH control agents to replace conventional CO\n                    <jats:sub>2<\/jats:sub>\n                    sparging, enabling simultaneous modulation of the bioreactor environment and cell metabolism. Carbon\u201013 metabolic flux analysis (\n                    <jats:sup>13<\/jats:sup>\n                    C\u2010MFA) revealed substantial rewiring of central carbon and nitrogen metabolism under all fed conditions, with distinct responses between cell lines. Intermediate\u2010fed cultures exhibited enhanced TCA cycle fluxes, reduced glucose dependency, decreased lactate accumulation, and altered routing of pyruvate. Notably, \u03b1\u2010ketoglutaric (\u03b1\u2010KG) acid feeding triggered divergent nitrogen assimilation phenotypes: one cell line enhanced glutamine biosynthesis and ammonium clearance, while the other accumulated glutamate with minimal glutamine production. These metabolic adaptations were accompanied by shifts in redox balance and delayed but measurable increases in cell\u2010specific IgG productivity. Our findings highlight the compound\u2010 and cell line\u2010specific nature of metabolic responses to TCA cycle intermediate feeding and support its use for pH control and bioprocess optimization.\n                  <\/jats:p>","DOI":"10.1002\/bit.70287","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T06:31:40Z","timestamp":1782714700000},"page":"2713-2728","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Flux Analysis Reveals Cell Line\u2010Specific Rewiring in CHO Cells Following TCA Cycle Intermediate Feeding for Bioprocess pH Control"],"prefix":"10.1002","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8256-7884","authenticated-orcid":false,"given":"Sarah A.","family":"Sacco","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering Vanderbilt University Nashville Tennessee USA"},{"name":"Biologics Process Research &amp; Development, Process Research &amp; Development Merck &amp; Co. 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Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7546-2208","authenticated-orcid":false,"given":"Kevin J.","family":"Ruiz\u2010M\u00e1rquez","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering Vanderbilt University Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7158-2106","authenticated-orcid":false,"given":"Rachel","family":"Moen","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering Vanderbilt University Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Trenary","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering Vanderbilt University Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Biologics Process Research &amp; Development, Process Research &amp; Development Merck &amp; Co. 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