Malic enzyme 1 senses L-lactate to determine tumor heterogeneity.

Authors

Si-Yi Cao, Kewen Hu, Shijing Huang, Xiao-Lin Guan, Jian Wang, Yuan Shen, Hui Ming, Aihong Gu, Chao Wang, Xiao Shen, Qing Wu, Zhengjun Chen, Miao Yin, Wenyu Wen, Qun-Ying Lei

Published in

Signal transduction and targeted therapy. Volume 11. Issue 1. Sep 11, 2026. Epub Sep 11, 2026.

Abstract

L-lactate is generally elevated in tumors and acts as a signaling molecule that promotes tumor progression. Here, we reveal that malic enzyme 1 (ME1) functions as a previously unrecognized sensor of L-lactate through direct binding at arginine 155 (R155), thereby potentiating malignancy. Mechanistically, L-lactate binding promotes the nuclear translocation of ME1, a process involving reduced acetylation at lysine 362 (K362) and facilitated by nuclear import of karyopherin-α 4 (KPNA4). Nuclear accumulation of ME1 enhances metastatic potential, which is correlated with increased interaction with hepatoma-derived growth factor (HDGF) and acquisition of an epithelial‒mesenchymal transition (EMT)-related phenotype. Under nutrient-deficient conditions, L-lactate promotes the assembly of a ME1-lactate dehydrogenase B (LDHB) complex, which enhances oxidative phosphorylation (OXPHOS) and increases ATP production, suggesting a metabolic adaptive mechanism that supports tumor cell survival. Notably, the ME1^R155A mutation, which disrupts L-lactate binding, abolishes the protumorigenic effect of the L-lactate-ME1 axis on tumor progression in vivo. In conclusion, our findings identify ME1 as a direct sensor of L-lactate and support a model in which lactate-mediated signaling and metabolic adaptation converge on ME1 to regulate tumor cell plasticity in a context-dependent manner under heterogeneous metabolic conditions. These insights advance our understanding of the spatiotemporal control of metabolic adaptation in cancer and reveal a potential therapeutic target.

PMID:
42728262
Bibliographic data and abstract were imported from PubMed on 12 Sep 2026.

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