ZEB1-TEAD1 partnership keeps heart cells fueled and functioning

A heart-specific transcription factor called ZEB1 helps keep cardiac muscle cells supplied with energy, and losing it drives the heart into failure, according to a study published in Nature Communications. The researchers report that ZEB1 expression is reduced in failing cardiomyocytes, and that mice lacking Zeb1 specifically in cardiomyocytes develop progressive heart failure accompanied by impaired glycolysis and fatty acid metabolism, the two main fuel-burning pathways that keep the beating heart running.

ZEB1, a zinc finger E-box binding homeobox 1 protein, was originally known as a regulator of epithelial-mesenchymal transition but has recently been implicated in metabolic control. In the new work, the team identified the mechanism behind its cardiac role: ZEB1 physically interacts with TEA domain transcription factor 1 (TEAD1), and together the two proteins activate metabolic genes. Among the key targets are pyruvate kinase muscle isozyme 1, or PKM1, which supports glycolysis, and acetyl-CoA acyltransferase 2, or ACAA2, which is required for fatty acid beta-oxidation.

The functional importance of this axis was tested in several ways. Loss of Acaa2 aggravated stress-induced cardiac hypertrophy and mitochondrial dysfunction, indicating that the fatty-acid burning machinery downstream of ZEB1 is itself protective under cardiac stress. Conversely, supplementing the animals with acetate, a metabolite that can feed into cellular energy production, restored cardiac function in Zeb1-deficient mice, suggesting that the failure caused by ZEB1 loss stems at least partly from an energy supply problem that can be bypassed metabolically.

The findings also point toward potential interventions, though they remain at the preclinical stage in mice. When the researchers overexpressed ZEB1, the animals showed improved outcomes in two distinct models of cardiac injury: pressure overload-induced heart failure, which mimics the strain produced by chronic high blood pressure, and doxorubicin-induced heart failure, a model of chemotherapy-related cardiac toxicity.

Overall, the study identifies the ZEB1-TEAD1 axis as a regulator of cardiac metabolic homeostasis and proposes it as a candidate therapeutic target for heart failure. Because metabolic reprogramming is increasingly recognized as a central feature of the failing heart, a transcriptional switch controlling both sugar and fat utilization in cardiomyocytes offers a single point of leverage over multiple energy pathways. The evidence so far comes from mouse models and cell-level mechanistic work, and further studies would be needed to establish whether the same axis operates in human heart failure and whether acetate supplementation or ZEB1-targeting approaches could be translated safely into treatment.

Subject of Research: The role of the ZEB1-TEAD1 transcriptional axis in cardiac energy metabolism and heart failure

Article Title: ZEB1 maintains energy metabolism to sustain cardiac function through synergistic regulation with TEAD1

Article References: Chen, T., Wu, Z., Liao, F., Shen, Y., Wang, Z., Qian, Y., Luo, G., Xu, W., He, X., Huang, Y., Chen, J., Xu, B., Ding, S., & Pu, J. (2026). ZEB1 maintains energy metabolism to sustain cardiac function through synergistic regulation with TEAD1. Nature Communications. https://doi.org/10.1038/s41467-026-78866-2

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78866-2

Keywords: ZEB1, TEAD1, heart failure, cardiac metabolism, glycolysis, fatty acid oxidation, PKM1, ACAA2, cardiomyocytes, acetate supplementation, mitochondrial dysfunction, Nature Communications