Abstract
<jats:p>Therapy resistance in acute myeloid leukemia (AML) is linked to metabolic plasticity and mitochondrial fitness of leukemic stem and progenitor cells. Clever-1 is a scavenger receptor with established immunoregulatory functions, but its leukemia cell-intrinsic roles remain unclear. Here we identify Clever-1 as a regulator of mitochondrial integrity and lipid-dependent oxidative metabolism in AML. Using the anti—Clever-1 antibody bexmarilimab, we show that Clever-1 inhibition induces early mitochondrial transcriptional reprogramming, followed by suppression of oxidative phosphorylation (OXPHOS) in AML cell lines. Immunoelectron microscopy demonstrates mitochondrial localization of Clever-1, while proteomic analyses reveal altered association with mitochondrial-linked proteins, including ATAD3. Functionally, Clever-1 inhibition reduces mitochondrial delivery of lipoprotein-derived lipids, resulting in selective changes in mitochondrial lipid composition. These changes are accompanied by impaired respiratory complex IV assembly, disrupted cristae architecture, accumulation of dysfunctional mitochondria, and reduced spare respiratory capacity. AML models with high baseline OXPHOS activity are particularly sensitive to Clever-1 inhibition, with mitochondrial dysfunction exacerbated under lipid-restricted or metabolically stressful conditions. Together, these findings define Clever-1 as a regulator of mitochondrial bioenergetic resilience and a targetable metabolic vulnerability in AML.</jats:p>