biostudies-literatureUnknown29(1)Kravtsova OMalonyl-CoA decarboxylase (MCD), encoded by <i>Mlycd</i>, plays a critical role in regulating malonyl-CoA levels, fatty acid oxidation, and glucose metabolism. To investigate the systemic effects of <i>Mlycd</i> deficiency, we generated a genetically modified rat model with partial loss of <i>Mlycd</i>. Due to high preweaning mortality in homozygous mutants, we focused on heterozygous and wild-type animals for cross-tissue targeted proteomic and metabolomic analyses. Alterations in metabolic and stress-related pathways were observed across the heart, kidney, liver, plasma, and urine. Enrichment of oxidative phosphorylation, fatty acid metabolism, immune responses, and autophagy-related signaling was noted. Elevated levels of oxidative stress-related proteins and disrupted autophagy regulatiScience114505https://www.ebi.ac.uk/biostudies/studies/S-EPMC12808911biostudies-literatureMCD enzyme deficiency drives early mortality and multiorgan metabolic disruption in Dahl salt-sensitive rats.PMC12808911Rinschen MMLevchenko VTiwari RZietara ASharp TEStaruschenko ADissanayake LVPalygin OBohovyk RTan YVan TTGeurts AMKravtsova OKovalenko EfalseMCD enzyme deficiency drives early mortality and multiorgan metabolic disruption in Dahl salt-sensitive rats.Malonyl-CoA decarboxylase (MCD), encoded by <i>Mlycd</i>, plays a critical role in regulating malonyl-CoA levels, fatty acid oxidation, and glucose metabolism. To investigate the systemic effects of <i>Mlycd</i> deficiency, we generated a genetically modified rat model with partial loss of <i>Mlycd</i>. Due to high preweaning mortality in homozygous mutants, we focused on heterozygous and wild-type animals for cross-tissue targeted proteomic and metabolomic analyses. Alterations in metabolic and stress-related pathways were observed across the heart, kidney, liver, plasma, and urine. Enrichment of oxidative phosphorylation, fatty acid metabolism, immune responses, and autophagy-related signaling was noted. Elevated levels of oxidative stress-related proteins and disrupted autophagy regulat2026-01-01T00:00:00Z2026 Jan2026-06-06T16:01:29.591Z2026-06-02T03:09:40.036ZS-EPMC128089114155075210.1016/j.isci.2025.114505