Abstract Body: After intracerebral hemorrhage (ICH), red blood cells (RBCs) are engulfed by phagocytes, but many lyse beforehand, releasing toxic heme. Heme, a lipophilic molecule, embeds in cell plasma membranes (PM), inducing ferroptosis—a form of programmed cell death driven by iron-dependent peroxidation of membrane phospholipids. Macrophages are critical for erythrophagocytosis and recovery after ICH, and their ability to resist ferroptosis may be key to detoxifying the brain. We hypothesize that metabolic adaptations allow macrophages to resist heme-induced ferroptosis. Methods: Murine bone marrow-derived macrophages (BMDMs) were exposed to heme or senescent RBCs with or without inhibitors. Results: Exposure to heme or senescent RBCs induced upregulation of NADPH synthesis genes, including G6pd and Pgd from the Pentose Phosphate Pathway, and Me1 (Fig1A-F). Inhibiting G6pd or Me1 increased cell death, indicating that enhanced NADPH synthesis, crucial for heme degradation and oxidation defense, is essential for macrophages to resist ferroptosis (Fig1G&H). The mechanism by which free heme induces ferroptosis is unclear. Preliminary data suggest that heme-containing oxidized PM is removed by endocytosis and digested in lysosome-fused endosomes. Inhibiting lysosome acidification with Bafilomycin prevents cell death after heme treatment, disrupts macrophage metabolic adaptation, and reduces Hmox1 expression (Fig2A-E), implying that heme release from endolysosomes is necessary for ferroptosis. Inhibiting Hmox1 with SnPP or chelating iron with BIPY protects macrophages from ferroptosis, identifying iron from heme degradation as the trigger for ferroptosis by engulfed heme (Fig2F&G). Previously, longitudinal transcriptional profiling of CD14+ monocytes/macrophages from patient hematomas revealed a strong proinflammatory profile. Through additional analysis, we found altered iron metabolism skewed toward iron sequestration, marked by downregulation of Slc40a1, the iron export channel, and reduced expression of G6pd and Pgd (Fig3A-C). To mimic the proinflammatory profile of human ICH macrophages, we treated BMDMs with LPS. Inflammation decreased Slc40a1 and disrupted metabolic adaptation, mimicking the macrophage profile seen in ICH patients (Fig3D-G). TLR4 inhibition by TAK-242 restored both ferroptosis resistance and metabolic balance, indicating that inflammation impairs the metabolic adjustments essential for macrophages to resist ferroptosis after ICH (Fig3D-H).