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Highlights d Genetic screens identify transcription factors that regulate amino acid response pathway d ZBTB1 is necessary for the leukemic cell response to asparagine deprivation d ZBTB1 directly binds to ASNS promoter and promotes its transcription d Loss of ZBTB1 sensitizes T cell leukemia cells to Lasparaginase in vivo

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Iron is the most abundant transition metal in cells and essential for a wide range of biochemical processes. While most mammalian cells take up iron through receptor-mediated endocytosis of transferrin, molecular players involved in iron utilization under iron-limiting conditions are incompletely understood. To address this, we performed several parallel metabolism-focused CRISPRa gain of function screens, which revealed metabolic limitations under stress conditions. Screens for iron restriction identified expected members of iron utilization pathways, but also SLCO2B1, a poorly characterized membrane carrier. Expression of SLCO2B1 is sufficient to increase intracellular iron stores, bypass the essentiality of transferrin receptor-mediated iron uptake and enable cell proliferation under iron restriction. Mechanistically, SLCO2B1 mediates heme-analog import in cellular assays. Heme uptake by SLCO2B1 provides sufficient iron for cell proliferation through heme oxygenases. Notably, SLCO2B1 is predominantly expressed in microglia in the brain and primary microglia from Slco2b1-/- mice exhibit a strong defect in heme analog import. Altogether, our work identifies SLCO2B1 as a microglia-enriched plasma membrane heme importer and provides a genetic platform to identify metabolic limitations under stress conditions.