ACLY‐Driven Metabolic Reprogramming Promotes Histone Acetylation and Inflammation‐Associated Fibrosis in Chronic Kidney Disease

ABSTRACT The mechanisms by which metabolic stress drives epigenetic dysregulation and fibrosis in chronic kidney disease (CKD) remain incompletely understood. Using quantitative histone proteomics in murine fibrosis models, we uncovered a selective increase in histone H3 lysine 27 acetylation (H3K27ac) as a conserved epigenetic feature. Unbiased metabolomics revealed citrate accumulation, nominating ATP‐citrate lyase (ACLY) as a driver of acetyl‐CoA‐dependent histone acetylation. In murine models of folic acid and unilateral ureteral obstruction, ACLY expression, acetyl‐CoA levels, and H3K27ac were increased in injured kidneys. Tubule‐specific Acly deletion reduced acetyl‐CoA, H3K27ac, and attenuated tubulointerstitial fibrosis. Chromatin accessibility profiling revealed that loss of Acly decreased accessibility at pro‐inflammatory loci, including Jak1 and Jak2 , with reduced transcriptional output. These transcriptional and epigenetic signatures were observed in human CKD samples, where higher ACLY expression correlated with worse kidney function and increased JAK1/2 expression. Notably, ACLY inhibitors, including bempedoic acid and BMS‐303141 recapitulated the antifibrotic effects of Acly deletion in vivo in mice, supporting the therapeutic repurposing of ACLY inhibitors for CKD. Together, our findings position ACLY as a key metabolic‐epigenetic checkpoint of kidney fibrosis and a promising, druggable target for halting CKD progression.