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

Metabolic reprogramming plays a critical role in heart failure (HF), but its regulatory mechanisms remain incompletely understood. Zinc finger E-box binding homeobox 1 (ZEB1), a transcription factor initially identified as a regulator of epithelial-mesenchymal transition, has recently been implicated in metabolic regulation. Here, we show that ZEB1 expression is reduced in failing cardiomyocytes. Cardiomyocyte-specific deletion of Zeb1 leads to progressive HF with impaired glycolysis and fatty acid metabolism. Mechanistically, ZEB1 interacts with TEA domain transcription factor 1 (TEAD1) to activate metabolic genes, including pyruvate kinase muscle isozyme 1 (PKM1) and acetyl-CoA acyltransferase 2 (ACAA2), which regulate glycolysis and fatty acid β-oxidation, respectively. Loss of Acaa2 aggravates stress-induced cardiac hypertrophy and mitochondrial dysfunction. Acetate supplementation restores cardiac function in Zeb1-deficient mice, whereas ZEB1 overexpression improves pressure overload- and doxorubicin-induced HF. These findings identify the ZEB1-TEAD1 axis as a regulator of cardiac metabolic homeostasis and a potential therapeutic target for HF. Heart failure is a major health challenge, and the mechanisms driving metabolic dysfunction in the failing heart remain poorly understood. Here, the authors show that ZEB1-TEAD1 signaling preserves cardiac energy metabolism and that restoring ZEB1 or supplementing its downstream metabolite acetate mitigates heart failure progression.