Related Experiment Video
Updated: Apr 18, 2026
06:23
Modeling Hypoxia/Reoxygenation Injury in Proximal Tubular Epithelial Cells
Published on: November 21, 2025
711
ACLY-Driven Metabolic Reprogramming Promotes Histone Acetylation and Inflammation-Associated Fibrosis in Chronic
Chunxiu Du1,2,3, Dhanunjay Mukhi1,2,3, Lingzhi Li1,2,3
1Institutes for Diabetes, Obesity and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 16, 2026
Summary
Metabolic stress drives kidney fibrosis via epigenetic changes. ATP-citrate lyase (ACLY) inhibition reduces fibrosis by decreasing histone acetylation, offering a therapeutic target for chronic kidney disease (CKD).
Area of Science:
- Nephrology
- Epigenetics
- Metabolic pathways
Background:
- Chronic kidney disease (CKD) pathogenesis involves metabolic stress and epigenetic dysregulation.
- The precise mechanisms linking metabolic stress to kidney fibrosis are not fully understood.
Purpose of the Study:
- To investigate the role of metabolic pathways in driving epigenetic changes and fibrosis in CKD.
- To identify potential therapeutic targets for halting CKD progression.
Main Methods:
- Quantitative histone proteomics and unbiased metabolomics in murine fibrosis models.
- Tubule-specific gene deletion and chromatin accessibility profiling.
- Analysis of human CKD samples and therapeutic efficacy of ACLY inhibitors.
Main Results:
- Increased histone H3 lysine 27 acetylation (H3K27ac) and citrate accumulation were identified as conserved features in kidney fibrosis.
- ATP-citrate lyase (ACLY) was identified as a key driver of histone acetylation and kidney fibrosis.
- ACLY inhibition or deletion attenuated fibrosis, reduced pro-inflammatory gene expression (JAK1/2), and improved kidney function in murine models.
- ACLY expression correlated with kidney dysfunction and JAK1/2 expression in human CKD.
Conclusions:
- ACLY is a critical metabolic-epigenetic regulator linking metabolic stress to kidney fibrosis.
- Targeting ACLY with inhibitors represents a promising therapeutic strategy for managing CKD progression.
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