Jimena López, SamuelVicente Sánchez, JavierBenito Sáez, SantiagoMarquina Díaz, DomingoSantos de la Sen, Antonio2025-10-072025-10-072025-09Jimena-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.2025.100301.10.1016/j.fochms.2025.100301https://hdl.handle.net/20.500.14352/124626Acknowledgements 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.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal article2666-5662https://doi.org/10.1016/j.fochms.2025.100301https://www.sciencedirect.com/science/article/pii/S2666566225000620open access579.67577.15Lachancea thermotoleransChemical compositionMetabolic inhibitorsLactic fermentationLactic acidTranscriptomeMicrobiología (Biología)Bioquímica (Biología)Biotecnología2414 Microbiología3309.90 Microbiología de Alimentos3309.92 Bioquímica y Microbiología de Los Procesos Fermentativos