ALKBH3-regulated m1A of ALDOA potentiates glycolysis and doxorubicin resistance of triple negative breast cancer cells

https://doi.org/10.1016/j.apsb.2025.04.018

This new article publication from Acta Pharmaceutica Sinica B, discusses how ALKBH3-regulated m¹A of ALDOA potentiates glycolysis and doxorubicin resistance of triple negative breast cancer cells.

Chemotherapy is currently the mainstay of systemic management for triple-negative breast cancer (TNBC), but chemoresistance significantly impacts patient outcomes.

This research indicates that Doxorubicin (Dox)-resistant TNBC cells exhibit increased glycolysis and ATP generation compared to their parental cells, with this metabolic shift contributing to chemoresistance. It was discovered that ALKBH3, an m¹A demethylase enzyme, is crucial in regulating the enhanced glycolysis in Dox-resistant TNBC cells.

Knocking down ALKBH3 reduced ATP generation, glucose consumption, and lactate production, implicating its involvement in mediating glycolysis. Further investigation revealed that aldolase A (ALDOA), a key enzyme in glycolysis, is a downstream target of ALKBH3. ALKBH3 regulates ALDOA mRNA stability through m¹A demethylation at the 3′-untranslated region (3′UTR). This methylation negatively affects ALDOA mRNA stability by recruiting the YTHDF2/PAN2–PAN3 complex, leading to mRNA degradation. The ALKBH3/ALDOA axis promotes Dox resistance both in vitro and in vivo.

Clinical analysis demonstrated that ALKBH3 and ALDOA are upregulated in breast cancer tissues, and higher expression of these proteins is associated with reduced overall survival in TNBC patients. This study highlights the role of the ALKBH3/ALDOA axis in contributing to Dox resistance in TNBC cells through regulation of ALDOA mRNA stability and glycolysis. 

Keywords: Glycolysis, Chemoresistance, ALKBH3, m¹A, ALDOA, Stability, TNBC, 3′UTR

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383525002758-ga1_lrg.jpg

This study reports that ALKBH3 regulates glycolysis in doxorubicin-resistant TNBC cells through m¹A methylation of ALDOA mRNA. Specifically, m¹A methylation negatively regulated ALDOA mRNA stability by recruiting the YTHDF2/PAN2–PAN3 complex.

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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.

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CiteScore: 24.3

Impact Factor: 14.6 (Top 6 journal in the category of Pharmacology and pharmacy) 

JIF without self-citation: 13.8

ISSN 2211-3835

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Yuhua Deng, Zhiyan Chen, Peixian Chen, Yaming Xiong, Chuling Zhang, Qiuyuan Wu, Huiqi Huang, Shuqing Yang, Kun Zhang, Tiancheng He, Wei Li, Guolin Ye, Wei Luo, Hongsheng Wang, Dan Zhou, ALKBH3-regulated m1A of ALDOA potentiates glycolysis and doxorubicin resistance of triple negative breast cancer cells, Acta Pharmaceutica Sinica B, Volume 15, Issue 6, 2025, Pages 3092-3106, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2025.04.018