Heme excess impairs macrophage phagocytic capacity. In anti-inflammatory macrophages, effective efferocytosis is achieved through PPARγ/PCG1α that induce the expression of efferocytic receptors and promote a metabolic rewiring toward oxidative phosphorylation (OXPHOS) sustained by fatty acid oxidation (FAO). In SCD, heme excess, by inhibiting PPARγ/PCG1α, leads to the diminished expression of efferocytic receptors and favors glycolytic metabolism that in turn sustains a proinflammatory phenotype. Both heme scavenging and pharmacological modulation of PPARγ/PCG1α improve efferocytosis in heme overloaded macrophages. Created with BioRender.com.