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Therefore, the present study explores the use of pyruvate dehydrogenase kinase (PDK) inhibitors dichloroacetate (DCA), metformin (M), (S)\u20103,3,3\u2010trifluoro\u20102\u2010hydroxy\u20102\u2010methyl propionic acid (TPP), and 4\u2010phenylbutyrate (PB) to counteract this metabolic bottleneck. To achieve optimal mAb yields, individual inhibitors (0.5\u201310\u2009mM) were screened, followed by evaluation of their combinatorial effects. A combination of 5\u2009mM DCA and 1\u2009mM TPP (DCA\u2009+\u2009TPP) revealed ~2\u2010fold enhancement in mAb yield (1.2\u2009g\/L) under fed\u2010batch conditions, accompanied by a marked reduction in lactate accumulation as compared to control. The optimized DCA\u2009+\u2009TPP combination also exhibited 15%\u201320% enhancement in the mAb yield as compared to a single PDK inhibitor that is, DCA (5\u2009mM) and TPP (1.0\u2009mM) at the same concentration. Metabolic analysis revealed a 19.5\u2010fold increase in pyruvate flux and a 2\u2010fold increase in intracellular acetyl\u2010CoA. The critical product quality attributes exhibited insignificant impact on charge variant (&lt;3%), aggregation, and glycosylation of mAb. The amino acid consumption profiles predominantly showed depletion of glycine and tryptophan, whereas threonine and aspartic acid were primarily consumed in the control. Proteomic analysis exhibited upregulation and downregulation of various proteins, which significantly contribute to mAb's yield. Validation in Trastuzumab\u2010producing CHO\u2010S cells confirmed a 30% increase in mAb yield and a 10% improvement in cell density. These outcomes demonstrate that the combination of DCA\u2009+\u2009TPP is a promising metabolic intervention to mitigate the Warburg effect and enhance recombinant protein production in mammalian systems.<\/jats:p>","DOI":"10.1002\/btpr.88536","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T03:34:13Z","timestamp":1783568053000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Warburg effect in Chinese hamster ovary cell culture with pyruvate dehydrogenase kinase inhibitors"],"prefix":"10.1002","volume":"42","author":[{"given":"Geetanjali Basavaraj","family":"Hubli","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering Indian Institute of Technology Delhi  Hauz Khas India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richa","family":"Katiyar","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering 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