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Metabolic-inhibitor profiling links phenotype and transcriptome of Lachancea thermotolerans to wine fermentation chemistry Jimena López, Samuel Vicente Sánchez, Javier Benito Sáez, Santiago Marquina Díaz, Domingo Santos de la Sen, Antonio 579.67 577.15 Lachancea thermotolerans Chemical composition Metabolic inhibitors Lactic fermentation Lactic acid Transcriptome Microbiología (Biología) Bioquímica (Biología) Biotecnología 2414 Microbiología 3309.90 Microbiología de Alimentos 3309.92 Bioquímica y Microbiología de Los Procesos Fermentativos Acknowledgements Funding for this research was provided by the LowpHWine Companies Consortia through the CDTI project LowpHWine (IDI-20210391) and the Spanish Ministry of Science and Innovation under the VinSegCalClim project (PID2020-119008RB-I00). Javier Vicente conducted this research under a fellowship from Complutense University of Madrid (CT58/21-CT59/21). Samuel Jimena conducted this research under an INVESTIGO (CT19/23-INVM-18) contract from the Spanish Ministry of Labour and Social Economy. We applied targeted metabolic inhibitors to 145 Lachancea thermotolerans strains to uncover fermentation traits with direct relevance to wine quality. Oxamate, a lactate dehydrogenase inhibitor, reduced lactic acid and total titratable acidity by 21% and 26%, respectively, while increasing succinic acid and pH without affecting ethanol levels, offering a promising strategy to fine-tune wine freshness and balance. Notably, industrial grape-associated strains (clusters C4–C6) maintained robust growth under oxamate stress, unlike wild strains, positioning oxamate resistance as a practical marker for selecting high-performing, acidifying yeasts for winemaking. Additional inhibitors such as metformin shifted redox metabolism, significantly enhancing glycerol (+25%) and acetic acid (+319%) production. Transcriptomic analyses showed that OXA alone, and even more so the DSF + OXA combination, repressed LDH2 and upregulated GPD1 and oxidative phosphorylation genes, whereas MET caused only moderate changes. This integrated phenomic-transcriptomic approach not only provides valuable tools for yeast screening but also defines a roadmap for optimizing wine composition through the precision selection of L. thermotolerans strains. Ministerio de Ciencia e Innovación (España) Ministerio de Trabajo y Economía Social (España) Universidad Complutense de Madrid Consorcio LowpHWine Depto. de Genética, Fisiología y Microbiología Fac. de Ciencias Biológicas TRUE pub 2025-10-07T17:26:52Z 2025-10-07T17:26:52Z 2025-09 journal article VoR https://hdl.handle.net/20.500.14352/124626 XXXX-XXXX 10.1016/j.fochms.2025.100301 2666-5662 eng PID2020-119008RB-I00 Jimena-López S, Vicente J, Benito S, Marquina D, Santos A. Metabolic-inhibitor profiling links phenotype and transcriptome of Lachancea thermotolerans to wine fermentation chemistry. Food Chemistry: Molecular Sciences 2025;11:100301. https://doi.org/10.1016/j.fochms.2025.100301. Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ open access application/pdf Elsevier