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Background Chronic cardiac pressure overload induces pathological remodeling, leading to heart failure (HF), a major global health burden. Despite decades of research, effective HF treatments remain limited, particularly those targeting metabolic reprogramming. Glycolysis alterations play a key role in the transition from compensatory hypertrophy to decompensated HF. Tbc1 domain family member 10c (Tbc1d10c) has been implicated in HF progression, while other Tbc1 family members regulate glucose metabolism in skeletal muscle and tumors. However, the role of Tbc1d10c in glycolysis during compensatory cardiac hypertrophy remains unclear. We aim to investigate the role of Tbc1d10c in cardiac glycolysis and its downstream mechanisms in the transition from compensatory hypertrophy to decompensated HF.Methods Cardiac-specific Tbc1d10c knockout mice were used to construct a transverse aortic constriction (TAC) model of heart failure. Single-cell RNA sequencing data were reanalyzed to characterize cardiomyocyte subtypes and Tbc1d10c expression across these subtypes in a time-series manner. Western blot, RT-qPCR, and immunofluorescence were employed to assess the mRNA and protein levels of relevant molecules.Results Tbc1d10c expression was significantly downregulated in human HF samples at both mRNA and protein levels, correlating with ejection fraction values. Single-cell RNA sequencing (scRNA-seq) of murine hearts revealed a progressive decline in Tbc1d10c expression and glycolysis scores across cardiomyocyte subtypes after transverse aortic constriction (TAC), suggesting a regulatory role of Tbc1d10c in metabolic remodeling. Cardiac-specific Tbc1d10c knockout led to HF, characterized by impaired compensatory hypertrophy, reduced ejection fraction, and compromised myocardial strain. Glycolysis was significantly impaired in Tbc1d10c-deficient hearts, with reduced glycolytic intermediates, downregulated glycolytic gene expression, and decreased glycolytic flux. Unbiased gene screening identified forkhead box K1 (Foxk1) as a key downstream regulator of Tbc1d10c. ChIP-seq data demonstrated Foxk1 binding to promoters of glycolytic genes, forming a glycolysis-related regulon. Foxk1 knockdown in neonatal rat ventricular myocytes (NRVMs) suppressed glycolytic enzyme expression and attenuated Tbc1d10c-induced cardiac hypertrophy. Mechanistically, Tbc1d10c regulated the cytoplasmic-to-nuclear shuttling of Foxk1 via the mTOR-GSK3α/β pathway. Under basal conditions, phosphorylated Foxk1 remains cytoplasmic. Upon mTOR-GSK3α/β-mediated dephosphorylation, Foxk1 translocates to the nucleus, promoting glycolytic gene transcription. Tbc1d10c deficiency disrupted this process, preventing Foxk1 nuclear translocation and impairing cardiac glycolysis. In vivo, Foxk1 overexpression via AAV9 rescued Tbc1d10c-deficient phenotypes, restoring glycolytic flux, upregulating glycolytic genes, and improving cardiac hypertrophy and function.Conclusions Tbc1d10c expression declines in HF, and its deletion disrupts Foxk1-mediated glycolysis, impairing compensatory cardiac hypertrophy and accelerating HF progression. These findings highlight Tbc1d10c as a potential therapeutic target, expanding HF treatment strategies beyond traditional approaches by restoring cardiac glycolysis.