Metabolic-Epigenetic Axis via ACLY Fuels Citrate-Induced Chromatin Activation in CKD Fibrosis

Background: Metabolic reprogramming is increasingly recognised as a central driver of tissue fibrosis, but the precise molecular links between altered metabolism and epigenetic control in chronic kidney disease (CKD) have remained elusive. ATP citrate lyase (ACLY) converts citrate to acetyl-CoA, supplying the substrate required for histone acetylation. We hypothesised that in CKD, accumulation of citrate and upregulation of ACLY create a metabolic-epigenetic feed-forward loop that promotes chromatin opening at profibrotic loci and drives disease progression. Methods: We used three mouse fibrosis models (0.2% adenine diet, folic acid-induced nephropathy, UUO) alongside human CKD biopsies (n=20, stages 2-5). Global histone marks were profiled by untargeted MS, and citrate/metabolites measured by metabolomics. Tubule-specific Acly knockout (Acly^flox/flox; Ksp-Cre) and an ACLY inhibitor assessed renal function (creatinine, BUN, collagen). Integrated ATAC-seq/RNA-seq compared chromatin accessibility and transcriptomes in KO versus controls, with mechanistic validation in human proximal tubule cells and kidney organoids. Results: CKD mouse models and human biopsies displayed a two fold increase in histone H3K27 acetylation and a 40% elevation of tissue citrate. ACLY protein and activity rose by 50%in diseased kidneys and correlated inversely with eGFR in patients. Tubule-specific Acly deletion reduced blood urea nitrogen by 30%, lowered fibrosis area by 60% (p < 0.01), and reversed CKD-associated transcriptional programs. ACLY inhibition in wild-type mice mirrored these benefits and restored chromatin compaction at key fibrotic gene promoters (Col1a, Fn1). ATAC-seq revealed closure of >1,200 regulatory regions enriched for SMAD and EP300 binding sites, with concordant downregulation of TGF-β target genes. In vitro, ACLY blockade diminished collagen secretion by 70% in primary human tubular cells and attenuated fibrotic marker expression in kidney organoids. Conclusion: These findings establish ACLY as a pivotal metabolic-epigenetic nexus in renal fibrosis. ACLY thus represents a compelling therapeutic target for CKD, with immediate translational potential via repurposing of existing ACLY inhibitors.