Quercetin inhibits the cAMP/PKA/CREB/glycolysis axis to exert anti-acute lymphoblastic leukemia effects
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 glycoly...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1614973/full |
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| author | Qiuling Ma Qiuling Ma Qiuling Ma Wenqing Liu Wenqing Liu Yajing Su Yajing Su Jue Guo Jue Guo Man Zhang Man Zhang Jiayuan Guo Jiayuan Guo Mingxin Liu Mingxin Liu Wenbo Dong Wenbo Dong Mingwei Li Mingwei Li Bo Wang Bo Wang |
| author_facet | Qiuling Ma Qiuling Ma Qiuling Ma Wenqing Liu Wenqing Liu Yajing Su Yajing Su Jue Guo Jue Guo Man Zhang Man Zhang Jiayuan Guo Jiayuan Guo Mingxin Liu Mingxin Liu Wenbo Dong Wenbo Dong Mingwei Li Mingwei Li Bo Wang Bo Wang |
| author_sort | Qiuling Ma |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2b441fa1b94e4532ada70723b640a0cf |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-2b441fa1b94e4532ada70723b640a0cf2025-08-20T02:59:41ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-08-011610.3389/fphar.2025.16149731614973Quercetin inhibits the cAMP/PKA/CREB/glycolysis axis to exert anti-acute lymphoblastic leukemia effectsQiuling Ma0Qiuling Ma1Qiuling Ma2Wenqing Liu3Wenqing Liu4Yajing Su5Yajing Su6Jue Guo7Jue Guo8Man Zhang9Man Zhang10Jiayuan Guo11Jiayuan Guo12Mingxin Liu13Mingxin Liu14Wenbo Dong15Wenbo Dong16Mingwei Li17Mingwei Li18Bo Wang19Bo Wang20The Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, ChinaDepartment of Hematology, Henan Province Hospital of Traditional Chinese Medicine (The Second Affiliated Hospital of Henan University of Chinese Medicine), Institute of Hematology, Henan University of Chinese Medicine, Zhengzhou, Henan, ChinaHe Nan Province Engineering Research Center of Integrative Medicine for the Prevention and Treatment of Hematological Diseases, Zhengzhou, Henan, ChinaThe Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, ChinaHe Nan Province Engineering Research Center of Integrative Medicine for the Prevention and Treatment of Hematological Diseases, Zhengzhou, Henan, ChinaThe Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, ChinaHe Nan Province Engineering Research Center of Integrative Medicine for the Prevention and Treatment of Hematological Diseases, Zhengzhou, Henan, ChinaThe Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, ChinaHe Nan Province Engineering Research Center of Integrative Medicine for the Prevention and Treatment of Hematological Diseases, Zhengzhou, Henan, ChinaThe Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, ChinaHe Nan Province Engineering Research Center of Integrative Medicine for the Prevention and Treatment of Hematological Diseases, Zhengzhou, Henan, ChinaThe Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, ChinaHe Nan Province Engineering Research Center of Integrative Medicine for the Prevention and Treatment of Hematological Diseases, Zhengzhou, Henan, ChinaThe Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, ChinaHe Nan Province Engineering Research Center of Integrative Medicine for the Prevention and Treatment of Hematological Diseases, Zhengzhou, Henan, ChinaThe Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, ChinaHe Nan Province Engineering Research Center of Integrative Medicine for the Prevention and Treatment of Hematological Diseases, Zhengzhou, Henan, ChinaThe Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, ChinaHe Nan Province Engineering Research Center of Integrative Medicine for the Prevention and Treatment of Hematological Diseases, Zhengzhou, Henan, ChinaThe Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, ChinaHe Nan Province Engineering Research Center of Integrative Medicine for the Prevention and Treatment of Hematological Diseases, Zhengzhou, Henan, ChinaAcute 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.https://www.frontiersin.org/articles/10.3389/fphar.2025.1614973/fullacute lymphoblastic leukemiaquercetinglycolysisCAMP/PKA/CREBmetabolic reprogramming |
| spellingShingle | Qiuling Ma Qiuling Ma Qiuling Ma Wenqing Liu Wenqing Liu Yajing Su Yajing Su Jue Guo Jue Guo Man Zhang Man Zhang Jiayuan Guo Jiayuan Guo Mingxin Liu Mingxin Liu Wenbo Dong Wenbo Dong Mingwei Li Mingwei Li Bo Wang Bo Wang Quercetin inhibits the cAMP/PKA/CREB/glycolysis axis to exert anti-acute lymphoblastic leukemia effects Frontiers in Pharmacology acute lymphoblastic leukemia quercetin glycolysis CAMP/PKA/CREB metabolic reprogramming |
| title | Quercetin inhibits the cAMP/PKA/CREB/glycolysis axis to exert anti-acute lymphoblastic leukemia effects |
| title_full | Quercetin inhibits the cAMP/PKA/CREB/glycolysis axis to exert anti-acute lymphoblastic leukemia effects |
| title_fullStr | Quercetin inhibits the cAMP/PKA/CREB/glycolysis axis to exert anti-acute lymphoblastic leukemia effects |
| title_full_unstemmed | Quercetin inhibits the cAMP/PKA/CREB/glycolysis axis to exert anti-acute lymphoblastic leukemia effects |
| title_short | Quercetin inhibits the cAMP/PKA/CREB/glycolysis axis to exert anti-acute lymphoblastic leukemia effects |
| title_sort | quercetin inhibits the camp pka creb glycolysis axis to exert anti acute lymphoblastic leukemia effects |
| topic | acute lymphoblastic leukemia quercetin glycolysis CAMP/PKA/CREB metabolic reprogramming |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1614973/full |
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