biostudies-literatureHan ZU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)NCI NIH HHS720-733https://www.ebi.ac.uk/biostudies/studies/S-EPMC12175649biostudies-literatureUnknown39(3)Multiple myeloma (MM) remains an incurable hematological malignancy that necessitates the identification of novel therapeutic strategies. Here, we report that intracellular levels of very long chain fatty acids (VLCFAs) control the cytotoxicity of MM chemotherapeutic agents. Inhibition of VLCFA biosynthesis reduced cell death in MM cells caused by the proteasome inhibitor, bortezomib. Conversely, inhibition of VLCFA degradation via suppression of peroxisomal acyl-CoA oxidase 1 (ACOX1) increased the cytotoxicity of bortezomib, its next-generation analog, carfilzomib, and the immunomodulatory agent lenalidomide. Furthermore, treatment with an orally available ACOX1 inhibitor cooperated with bortezomib in suppressing the growth of bortezomib-resistant MM xenografts in mice. Increased VLCFA leLeukemiaTargeting ABCD1-ACOX1-MET/IGF1R axis suppresses multiple myeloma.PMC12175649R01CA264984P30CA014236R01 CA264984R21CA280499Wu JLiu LBeus MLee JMa ZNikiforov MAHan ZCivils JDKang YYan ZLakhani KLu JWeidenhammer LBWang YFurdui CMBieberich EBoise LHfalseTargeting ABCD1-ACOX1-MET/IGF1R axis suppresses multiple myeloma.Multiple myeloma (MM) remains an incurable hematological malignancy that necessitates the identification of novel therapeutic strategies. Here, we report that intracellular levels of very long chain fatty acids (VLCFAs) control the cytotoxicity of MM chemotherapeutic agents. Inhibition of VLCFA biosynthesis reduced cell death in MM cells caused by the proteasome inhibitor, bortezomib. Conversely, inhibition of VLCFA degradation via suppression of peroxisomal acyl-CoA oxidase 1 (ACOX1) increased the cytotoxicity of bortezomib, its next-generation analog, carfilzomib, and the immunomodulatory agent lenalidomide. Furthermore, treatment with an orally available ACOX1 inhibitor cooperated with bortezomib in suppressing the growth of bortezomib-resistant MM xenografts in mice. Increased VLCFA le2025-01-01T00:00:00Z2025 Mar2026-05-29T17:13:46.114Z2026-04-08T05:30:23.11ZS-EPMC121756493988529510.1038/s41375-025-02522-9