Mah, C.Y.Nguyen, A.D.T.Niijima, T.Helm, M.Dehairs, J.Ryan, F.J.Ryan, N.Quek, L.-E.Hoy, A.J.Don, A.S.Mills, I.G.Swinnen, J.V.Lynn, D.J.Nassar, Z.D.Butler, L.M.2024-10-042024-10-042024British Journal of Cancer, 2024; 130(5):741-7540007-09201532-1827https://hdl.handle.net/2440/142700Published online: 12 January 2024BACKGROUND: Peroxisomes are central metabolic organelles that have key roles in fatty acid homoeostasis. As prostate cancer (PCa) is particularly reliant on fatty acid metabolism, we explored the contribution of peroxisomal β-oxidation (perFAO) to PCa viability and therapy response. METHODS: Bioinformatic analysis was performed on clinical transcriptomic datasets to identify the perFAO enzyme, 2,4-dienoyl CoA reductase 2 (DECR2) as a target gene of interest. Impact of DECR2 and perFAO inhibition via thioridazine was examined in vitro, in vivo, and in clinical prostate tumours cultured ex vivo. Transcriptomic and lipidomic profiling was used to determine the functional consequences of DECR2 inhibition in PCa. RESULTS: DECR2 is upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa (CRPC). Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and therapy-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. DECR2 influences cell cycle progression and lipid metabolism to support tumour cell proliferation. Further, co-targeting of perFAO and standard-of-care androgen receptor inhibition enhanced suppression of PCa cell proliferation. CONCLUSION: Our findings support a focus on perFAO, specifically DECR2, as a promising therapeutic target for CRPC and as a novel strategy to overcome lethal treatment resistance.en© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by/4.0/.Peroxisomal β-oxidationCell Line, TumorHumansFatty AcidsReceptors, AndrogenAndrogensCell ProliferationMaleLipid MetabolismProstatic Neoplasms, Castration-ResistantJournal article10.1038/s41416-023-02557-82024-04-23681506Mah, C.Y. [0000-0002-8820-4037]Nguyen, A.D.T. [0000-0001-7415-7754]Nassar, Z.D. [0000-0002-7779-2697]Butler, L.M. [0000-0003-2698-3220]