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There is a critical need to find new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we identified and explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. In our work, myeloma cells were treated with FABP inhibitors (BMS3094013 and SBFI-26) and examined in vivo and in vitro for cell cycle state, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation properties. Myeloma cell responses to BMS309403, SBFI-26, or both, were also assessed with RNA sequencing (RNA-Seq) and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using the Cancer Dependency Map (DepMap). Finally, MM patient datasets (CoMMpass and GEO) were mined for\n                    <jats:italic>FABP<\/jats:italic>\n                    expression correlations with clinical outcomes. We found that myeloma cells treated with FABPi or with\n                    <jats:italic>FABP5<\/jats:italic>\n                    knockout (generated via CRISPR\/Cas9 editing) exhibited diminished proliferation, increased apoptosis, and metabolic changes in vitro. FABPi had mixed results in vivo, in two pre-clinical MM mouse models, suggesting optimization of in vivo delivery, dosing, or type of FABP inhibitors will be needed before clinical applicability. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells in vitro. Clinical data demonstrated worse overall and progression-free survival in patients with high\n                    <jats:italic>FABP5<\/jats:italic>\n                    expression in tumor cells. Overall, this study establishes the FABP family as a potentially new target in multiple myeloma. In MM cells, FABPs have a multitude of actions and cellular roles that result in the support of myeloma progression. Further research into the FABP family in MM is warrented, especially into the effective translation of targeting these in vivo.\n                  <\/jats:p>","DOI":"10.7554\/elife.81184","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T06:15:35Z","timestamp":1676614535000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.81184","source":"Crossref","is-referenced-by-count":40,"title":["Targeting the fatty acid binding proteins disrupts multiple myeloma cell cycle progression and MYC signaling"],"prefix":"10.7554","volume":"12","author":[{"given":"Mariah","family":"Farrell","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine, Maine Health Institute for Research","place":["Scarborough, United States"]},{"id":[{"id":"https:\/\/ror.org\/01adr0w49","id-type":"ROR","asserted-by":"publisher"}],"name":"Graduate School of Biomedical Science and Engineering, University of Maine","place":["Orono, United 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