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Peroxisomal β-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer

Peroxisomes are central metabolic organelles that have key roles in fatty acid homeostasis, including β-oxidation, and emerging evidence has linked aberrant peroxisome metabolism to cancer development and progression. While targeting mitochondrial β-oxidation in prostate cancer (PCa) has gained significant attention in recent years, the contribution of peroxisomal β-oxidation (perFAO) to PCa tumorigenesis is comparatively unexplored. Herein, we explored the therapeutic efficacy of targeting perFAO in PCa cells and clinical prostate tumours, and subsequently identified peroxisomal 2,4-dienoyl CoA reductase 2 (DECR2), as a key therapeutic target. DECR2 is markedly upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa. Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and enzalutamide-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. Using transcriptomic and lipidomic analyses, we determined that DECR2 influences cell cycle progression and lipid metabolism to enable tumour cell proliferation. We further demonstrated a novel role for perFAO in driving resistance to standard-of-care androgen receptor pathway inhibition, using genetic and pharmacological approaches to alter DECR2/perFAO in treatment-resistant PCa cells. Our findings highlight a need to focus on peroxisomes to suppress tumour cell proliferation and reveal new therapeutic targets for advanced, treatment-resistant PCa.