Targeting scavenger receptor class B type 1 with a bioinspired ligand induces apoptosis or ferroptosis in AML Open Access

• Scavenger receptor class B type 1 is expressed in acute myeloid leukemia, and its overexpression may suggest a worse prognosis.

• We engineered HDL nanoparticles to disrupt cholesterol metabolism, inhibit protective antioxidant mechanisms, and induce ferroptosis.

Despite progress in research and treatment strategies for acute myeloid leukemia (AML), the prognosis for AML patients, particularly for individuals who are older than 60 years old and those with adverse risk factors, remains poor. Cellular receptors that impact cholesterol homeostasis may present a new target for treating AML. Scavenger receptor class B type 1 (SR-B1), which plays an important role in cellular cholesterol uptake and redox balance, is expressed by AML cells and correlates with poor patient outcomes. Previously, we targeted SR-B1 in various hematologic and solid malignancies with a synthetic bioinspired high-density lipoprotein nanoparticle (HDL NPs) ligand that disrupted cholesterol metabolism, inhibited protective antioxidant mechanisms, and induced ferroptosis. This study demonstrates that HDL NPs are effective at low nanomolar drug concentrations in AML, surpassing the effectiveness of cytarabine, a standard-of-care chemotherapy agent. The HDL NP reduced glutathione peroxidase 4 (GPx4), leading to reactive oxygen species accumulation, which causes some AML cells to undergo ferroptosis while others undergo apoptosis and pyroptosis. HDL NP treatment was synergistic with standard AML therapies, including cytarabine, venetoclax, and gilteritinib for fms-like tyrosine kinase 3 (FLT3) mutated leukemia cells. Notably, HDL NP treatment induced the differentiation of AML cells into mature granulocytes. Overall, this study provides a foundation for further investigations into the underlying mechanisms and clinical applications of SR-B1 targeting in AML treatment.