Key result
Fibroblast-targeted PDK4 knockdown alleviates post-MI cardiac fibrosis and improves function by suppressing histone lactylation.
Why the study?
Cardiac fibroblast heterogeneity has hindered mechanistic understanding of myocardial fibrosis across various heart diseases.
Does fibroblast-targeted PDK4 knockdown reduce cardiac fibrosis and improve cardiac function in post-MI mouse models?
Does fibroblast-targeted PDK4 knockdown reduce cardiac fibrosis and improve cardiac function in post-MI mouse models?
PDK4-mediated lactate production and histone lactylation drive profibrotic activation in cardiac fibroblasts, and targeted PDK4 knockdown mitigates post-MI cardiac fibrosis in mice.
Hypothesis-generating for PDK4-targeted antifibrosis post-MI; human translation and trials required before any clinical consideration.
Cardiac fibroblasts act as a key driver of myocardial fibrosis across various heart diseases, but the recently recognized heterogeneity within fibroblast populations has hindered mechanistic understanding. This study aimed to investigate the heterogeneity of cardiac fibroblasts and the underlying mechanisms in both healthy and diseased hearts. A total of 236,748 cardiac fibroblasts from single-cell transcriptomics data from 73 samples were integrated, clustered and annotated, followed by a comprehensive analysis of cell composition, RNA velocity, differential gene expression as well as Non-Negative Matrix Factorization (NMF) generated gene expression programs. Based on these results, we conducted immunoblotting, metabolomics analysis, Co-IP, ChIP-qPCR to examine the role of PDK4 during profibrotic activation in neonatal mouse primary cardiac fibroblasts. We also performed immunofluorescence, flow cytometry and echocardiography to evaluate the effect of PDK4 inhibition in MI mice. Eight major populations of cardiac fibroblasts were identified and divided into two lineages. Twelve meta-programs (MPs) of transcriptional profiles of cardiac fibroblasts were uncovered by NMF analysis and revealed a strong association between PDK4-mediated glycolysis and Extracellular Matrix (ECM) deposition. Subsequently, experiments in primary cardiac fibroblasts of neonatal mouse indicated that PDK4 promoted lactate production and Histone H3 lactylation, which in turn, increased TGF-β1 expression and ECM synthesis. In addition, inhibition of PDK4 could alleviate cardiac fibrosis and improve cardiac function in MI mice. Collectively, our study delineates cardiac fibroblast heterogeneity after myocardial infarction and identifies PDK4 as a key regulator of profibrotic activation. Our findings support a mechanistic model in which PDK4-mediated lactate production and histone lactylation are linked to expression of TGF-β1 and ECM synthesis in cardiac fibroblasts. Together with the antifibrotic effects of fibroblast-targeted PDK4 knockdown by AAV9 in vivo, these results position PDK4 as a mechanistically relevant and potentially actionable therapeutic target for myocardial fibrosis.
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Qi et al. (2026) studied Myocardial fibrosis. PDK4 knockdown (AAV9-shPdk4) vs. Sham or scrambled shRNA control was evaluated on Cardiac fibrosis and cardiac function. Fibroblast-targeted PDK4 knockdown alleviated cardiac fibrosis and improved cardiac function in myocardial infarction mice by reducing lactate production and histone lactylation-mediated TGF-β1 expression.
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