DECR2 (2,4-dienoyl-CoA reductase 2) is a peroxisomal enzyme that catalyzes the NADPH-dependent reduction of 2,4-dienoyl-CoA to trans-3-enoyl-CoA, serving as an auxiliary enzyme in fatty acid β-oxidation 1. The enzyme participates in the degradation of unsaturated fatty acids with double bonds in both even- and odd-numbered positions within peroxisomes, showing activity toward short, medium, and long-chain substrates including docosaheptaenoyl-CoA 1. DECR2 plays critical roles in lipid metabolism regulation and cellular processes. In prostate cancer, DECR2 is upregulated, particularly in metastatic castrate-resistant disease, where it supports tumor cell proliferation, migration, and treatment resistance by influencing cell cycle progression and lipid metabolism 1. The enzyme also regulates ferroptosis and immunotherapy efficacy, as DECR2 knockdown reduces T cell-mediated tumor killing and anti-PD-L1 therapy effectiveness 2. Clinically, DECR2 upregulation correlates with anti-PD-1 efficacy in melanoma patients, while gene deletions associate with worse outcomes 2. The enzyme has been identified as a potential therapeutic target for gastroesophageal reflux disease and shows associations with various cancers including Hodgkin lymphoma 34. Lipidomic studies demonstrate that DECR2 knockout produces distinct fatty acid-level phenotypes, confirming its central role in cellular lipid homeostasis 5.