ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1614973
This article is part of the Research TopicNovel Targets and Therapeutic Strategies for Overcoming Drug Resistance in Hematologic MalignanciesView all articles
Quercetin inhibits the cAMP/PKA/CREB/glycolysis axis to exert anti-acute lymphoblastic leukemia effects
Provisionally accepted
- Henan University of Chinese Medicine, Zhengzhou, Henan Province, China
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Acute lymphoblastic leukemia (ALL), an aggressive hematologic malignancy with high incidence and treatment resistance, demands novel therapeutic approaches.Enhanced glycolysis is a hallmark of metabolic reprogramming in ALL. Quercetin (Que) demonstrates broad antitumor effects by inhibiting glycolysis and cell proliferation.Previous studies have shown that Que significantly suppresses the proliferation of ALL cells and induces apoptosis; however, its mechanistic basis remains elusive. In this study, we demonstrate that Que triggers mitochondrial dysfunction, activating the intrinsic apoptosis pathway and inducing G2/M phase cell cycle arrest. Que markedly reduces glucose uptake, lactate production, and ATP synthesis in ALL cells, suggesting a dual inhibitory effect on both oxidative phosphorylation (OXPHOS) and glycolysis.Mechanistically, Que inhibits the cAMP/PKA/CREB axis, substantially reducing both mRNA and protein levels of glycolytic enzymes (HK2, PFKP, and PKM2). Notably, the PKA-specific agonist Sp-cAMP (50 μmol/L) completely rescues Que-mediated effects.Collectively, Que's dual pro-apoptotic and anti-proliferative actions through the cAMP/PKA/CREB/glycolysis axis establish a molecular foundation for Que -based ALL therapies. KEYWORD: acute lymphoblastic leukemia, quercetin, glycolysis, cAMP/PKA/CREB, metabolic reprogramming Introduction： Acute lymphoblastic leukemia (ALL) is a malignant proliferative disease of lymphocytes with blocked early differentiation, involving the bone marrow, blood, and extramedullary sites. It is primarily classified into B -lineage tumors, T-lineage tumors, and NK cell lineages (Malard & Mohty, 2020) . Recent data show an increasing
Keywords: Acute Lymphoblastic Leukemia, Quercetin, Glycolysis, CAMP/PKA/CREB, metabolic reprogramming
Received: 20 Apr 2025; Accepted: 30 Jun 2025.
Copyright: © 2025 Ma, Liu, Su, Guo, Zhang, Guo, Liu, Dong, Li and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yajing Su, Henan University of Chinese Medicine, Zhengzhou, 450008, Henan Province, China
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