Deguelin suppresses Nalm6 leukemia cell proliferation through lactate accumulation and ATP depletion

Acute lymphoblastic leukemia (ALL) is characterized by metabolic reprogramming, including elevated glycolysis and lactate production. Monocarboxylate transporter 1 (MCT1/SLC16A1) is frequently overexpressed in ALL, sustaining glycolytic flux to promote cell proliferation. While the natural flavonoid deguelin is known to induce necroptosis at high concentrations, the mechanisms underlying its anti-leukemic effects at lower, potentially more therapeutically relevant doses remain unclear.

Nalm6 cells were treated with deguelin (0.08-10 µM) for up to 72 h. Cell viability, apoptosis, cell cycle, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) were analyzed. We found that low concentration of deguelin significantly inhibited proliferation by inducing G2/M phase cell cycle arrest. This was associated with reduced ROS levels and loss of ΔΨm. Mechanistically, low concentration of deguelin activated the GSK-3β/AKT signaling pathway without inducing NF-κB/p70S6K phosphorylation. Furthermore, it concurrently downregulated lactate dehydrogenase A (LDHA) and MCT1 expression, leading to decreased intracellular lactate synthesis and influx, extracellular lactate accumulation, and ultimately, severe intracellular ATP depletion.

Our study reveals the mechanism of low concentration of deguelin in ALL. It acts not through classic necroptosis, but via coordinated cell cycle arrest and a unique "metabolic trap" caused by dual inhibition of lactate synthesis and transport. These findings reposition deguelin as a promising candidate for targeted therapy against metabolic vulnerabilities in B-ALL.