DECR1 (2,4-dienoyl-CoA reductase 1) is a mitochondrial auxiliary enzyme of fatty acid β-oxidation that catalyzes the NADPH-dependent reduction of 2,4-dienoyl-CoA to trans-3-enoyl-CoA, enabling metabolism of unsaturated fatty acids with double bonds at even and odd positions. DECR1 plays a critical role in regulating lipid homeostasis and cellular energetics by controlling polyunsaturated fatty acid (PUFA) oxidation and maintaining redox balance through modulation of phospholipid saturation 1. The enzyme has recently been identified as a calcium-regulated protein that binds calcium at physiologically relevant concentrations with substrate-specific affinity, suggesting direct calcium regulation of mitochondrial fatty acid oxidation 2. DECR1 expression is dysregulated in multiple malignancies: overexpression in prostate and breast cancers promotes treatment resistance and suppresses ferroptosis-mediated cell death through PUFA oxidation 34, while DECR1 downregulation sensitizes cancer cells to ferroptosis 15. Conversely, DECR1 has cardioprotective functions, as BMP9-mediated DECR1 upregulation promotes mitochondrial bioenergetics and mitigates myocardial infarction-induced cardiomyocyte injury 6. Clinically, DECR1 deficiency causes monogenic metabolic dysfunction-associated steatotic liver disease, establishing it as essential for hepatic lipid homeostasis 7. These findings position DECR1 as a key metabolic regulator with significant disease relevance across cancer and metabolic pathology.