Targeting lipid metabolic vulnerabilities with small-molecule inhibitors in acute myeloid leukemia: Emerging insights and therapeutic opportunities.

Metabolic reprogramming has recently been recognized as a hallmark of cancer. In acute myeloid leukemia (AML), clinically relevant metabolism-targeted therapies have primarily focused on inhibiting mitochondrial energy production; however, their clinical progress has been limited by substantial and nonspecific toxicity. Emerging evidence indicates that reprogramming of lipid metabolism represents a defining feature of leukemic transformation. Lipids not only serve as fundamental structural components of cellular membranes but also function as key signaling molecules and energy sources. In AML cells, lipid uptake, storage, and de novo synthesis are markedly increased, thereby supporting rapid proliferation, survival, and leukemic progression. Consequently, dysregulated lipid metabolism has attracted growing attention as a promising therapeutic vulnerability in AML. This review summarizes the conceptual framework underlying AML cell dependence on cholesterol, fatty acids (FAs), sphingolipids, and broader lipid metabolic pathways. We highlight recent advances in understanding aberrant lipid metabolic programs in AML, including alterations in cholesterol biosynthesis, FA uptake and lipogenesis, FA oxidation, and sphingolipid metabolism. Particular emphasis is placed on the regulatory mechanisms that maintain lipid metabolic homeostasis and how their disruption contributes to leukemogenesis and therapy resistance. Furthermore, we discuss emerging therapeutic strategies aimed at targeting lipid metabolic pathways, with a focus on small-molecule inhibitors that selectively interfere with lipid metabolism-associated enzymes and signaling networks. By delineating key molecular targets and their pharmacological inhibitors, this review highlights the potential of lipid metabolism-based interventions as innovative and effective treatment strategies for AML.