A-485 alleviates fibrosis and apoptosis in kidney by disrupting tandem activation of acetylation and phosphorylation on STAT3

Lysine acetylation, tightly regulated by the dynamic balance between lysine acetyltransferases (KATs) and deacetylases (KDACs), plays a critical role in cellular processes, yet its involvement in kidney diseases remains elusive due to inconsistent findings. While KDACs have been extensively studied, the role of KATs, particularly p300 and CREB-binding protein (CBP), in kidney diseases is underexplored. p300 and CBP are major KATs and key transcriptional coactivators that regulate gene expression through acetylation of histones and non-histone proteins. A-485, a potent and specific p300/CBP inhibitor, was employed to investigate their role in kidney disease. Pan-acetylation levels were evaluated in three kidney disease models: type 1 diabetes, type 2 diabetes, and unilateral ureteral obstruction (UUO). The UUO model exhibited the most pronounced upregulation of pan-acetylation in the kidney, prompting its selection for further investigation. A-485 treatment in UUO mice and cultured renal epithelial cells reduced pan-acetylation, alleviated renal fibrosis and apoptosis, and improved mitochondrial dysfunction. Mechanistically, A-485 deactivated STAT3 by inhibiting acetylation at the K685 site, which disrupted tyrosine 705 (Y705) phosphorylation, a critical step in STAT3 activation, without altering serine 727 (S727) phosphorylation or total STAT3 expression. This reveals a tandem regulatory mechanism involving acetylation and phosphorylation in STAT3 signaling during renal fibrosis. Our findings demonstrate that A-485 protects against renal fibrosis by targeting p300/CBP-mediated STAT3 acetylation, providing a strong rationale for its potential therapeutic application in kidney diseases. This study advances the understanding of molecular mechanisms underlying kidney diseases and highlights A-485 as a promising candidate for future therapeutic development.