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Peroxisomes regulate fatty acid oxidation (FAO) and oxidative homeostasis with growing relevance in hematologic malignancies. Recent studies show peroxisomal FAO (pFAO) is selectively elevated in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), sustaining cancer cell survival under metabolic and therapeutic stress. Elevated ACOX1, ABCD1\/2, CROT, and PEX5 expression underscores leukemia\u2010specific peroxisomal vulnerability; their pharmacologic or genetic inhibition disrupts lipid homeostasis, induces very\u2010long\u2010chain fatty acid accumulation, and drives oxidative stress and lipotoxicity. This selectively kills leukemia cells while sparing normal progenitors. pFAO blockade synergizes with chemotherapy drugs such as venetoclax and cytarabine, enabling exploitation of metabolic vulnerabilities to improve therapeutic outcomes. Upstream, PPAR isoforms transcriptionally link lipid ligand sensing to peroxisomal gene expression, though their precise role in governing pFAO in leukemia remains undefined. Integrating solid tumor and leukemia insights, peroxisomes emerge as dynamic lipid\u2010processing organelles coupling FAO, redox buffering, and inter\u2010organelle exchange to cancer persistence. Targeting peroxisome\u2010mediated lipid delivery offers a frontier for overcoming metabolic resilience and therapeutic resistance in leukemia.<\/jats:p>","DOI":"10.1002\/mnfr.70530","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T06:47:32Z","timestamp":1781506052000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Peroxisomal Lipid Metabolism as a Therapeutic Target in Leukemia"],"prefix":"10.1002","volume":"70","author":[{"given":"Ekaterina N.","family":"Parfenova","sequence":"first","affiliation":[{"name":"Department of Food Science University of Guelph  Guelph Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Spagnuolo","sequence":"additional","affiliation":[{"name":"Department of Food Science University of Guelph  Guelph Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,14]]},"reference":[{"key":"e_1_2_17_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416\u2010023\u201002557\u20108"},{"key":"e_1_2_17_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010025\u201002522\u20109"},{"key":"e_1_2_17_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.115"},{"key":"e_1_2_17_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI166644"},{"key":"e_1_2_17_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018\u2010020\u201000126\u2010z"},{"key":"e_1_2_17_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201016\u20100441"},{"key":"e_1_2_17_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010021\u201000489\u20102"},{"key":"e_1_2_17_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3483"},{"key":"e_1_2_17_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adn2804"},{"key":"e_1_2_17_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5201"},{"key":"e_1_2_17_12_1","doi-asserted-by":"crossref","unstructured":"E. 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