Baicalein suppresses the malignant progression of acute myeloid leukemia via ROS-dependent metabolic reprogramming: Mechanisms of differentiation induction and ferroptosis activation

Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy driven by metabolic reprogramming, including dysregulated aerobic glycolysis and reactive oxygen species (ROS) signaling, which promote disease progression and therapeutic resistance. Although baicalein (BC) has demonstrated anti-tumor potential in various cancers, its specific role and molecular mechanisms in AML remain unclear. This study aimed to elucidate the effects and regulatory mechanisms of BC in AML. Network pharmacology analysis predicted BC's involvement in ROS regulation, myeloid differentiation, metabolic processes, and ferroptosis. In vitro experiments revealed that BC inhibited HL-60 cell proliferation and induced G0/G1 cell cycle arrest. Low concentrations of BC promoted ROS accumulation and myeloid differentiation, as evidenced by elevated CD11b and CD14 levels, which were reversed by ROS inhibitors. High concentrations of BC triggered ferroptosis via the SLC7A11/GSH/GPX4 pathway, confirmed by molecular docking and SLC7A11 overexpression. BC also suppressed aerobic glycolysis at both low and high concentrations. In vivo, BC significantly inhibited tumor progression in an HL-60 xenograft model by suppressing aerobic glycolysis. These findings demonstrate that BC modulates AML progression through concentration-dependent ROS accumulation, inducing differentiation at low doses and ferroptosis at high doses, offering a novel strategy for targeting the metabolism-oxidative stress axis in AML therapy.

Keywords: Acute myeloid leukemia; Aerobic glycolysis; Baicalein; Differentiation; Ferroptosis; SLC7A11.