Zinc Enhances Aerobic Glycolysis in Breast Cancer via PKM2 Dimerization and Nuclear Localization

Zinc regulates breast cancer progression by modulating cellular proliferation and hormone-dependent signaling pathways, yet its role in glucose metabolic reprogramming remains incompletely understood. In our study, we found that elevated Zn2+ enhances aerobic glycolysis while markedly suppressing mitochondrial oxidative phosphorylation and inhibiting the pentose phosphate pathway. Transcriptomic profiling further reveals that Zn2+ treatment selectively upregulates glycolysis-associated genes, including the glucose transporter GLUT1 (SLC2A1) and pyruvate kinase, highlighting a coordinated shift toward glycolytic metabolism under zinc-replete conditions. Mechanistically, Zn2+ directly binds to pyruvate kinase M2 isoform (PKM2), stabilizing its dimeric state and promoting its nuclear translocation. Nuclear PKM2 subsequently enhances the transcription of glycolytic genes (i.e., LDHA). Consistent with this mechanism, Zn2+ treatment sensitizes tumor cells to the LDHA-specific small-molecule inhibitor NHI-2, resulting in a synergistic anti-tumor effect. Furthermore, the zinc efflux transporter ZnT1 (SLC30A1) is transcriptionally induced following Zn2+ exposure, functioning as a feedback mechanism to maintain zinc homeostasis. Conversely, ZnT1 knockdown leads to intracellular zinc accumulation, which further enhances aerobic glycolysis through similar mechanisms of PKM2 dimer stabilization and nuclear translocation. Collectively, this study elucidates a molecular mechanism by which zinc promotes aerobic glycolysis through direct binding to PKM2, stabilizing its dimeric conformation and facilitating its nuclear localization. These findings propose a therapeutic strategy that combines Zn2+ supplement with LDHA inhibition, revealing a previously unrecognized metabolic vulnerability that may be leveraged for precision oncology. Citation Format: Wenyou He, Jiali Xu, Yihuizhi Zhang, Weijian Ding, Xinyu Chen, Yirui Ye, Linyue Li, Baotong Zhang, Siyuan Xia. Zinc promotes aerobic glycolysis in breast cancer by promoting PKM2 dimerization and nuclear localization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2025.