II型肺泡细胞中Kat5缺失通过STAT6驱动的糖酵解重编程促进肺纤维化

Abstract

Pulmonary fibrosis (PF) remains a lethal progressive disease with poorly defined molecular drivers. Epithelial dysfunction and metabolic reprogramming contribute to PF, but the mechanistic link between these processes remains unclear. Here, we identify a Kat5-STAT6 epigenetic-metabolic axis that governs fibrotic progression. Kat5 directly acetylates STAT6 at lysine 636 (K636), thereby suppressing STAT6 dimerization, phosphorylation and nuclear translocation. In fibrotic lungs, STAT6 acetylation at K636 is reduced, leading to its hyperactivation. Activated STAT6 drives transcription of pro-glycolytic enzyme hexokinase 2 (HK2), promoting metabolic reprogramming in alveolar type II (ATII) cells and extracellular matrix deposition. ATII cell-specific restoration of Kat5 rescues STAT6 acetylation, normalizes its activity and ameliorates fibrosis in vivo. Mechanistically, Kat5-mediated STAT6 acetylation functions as a biochemical brake that limits cooperation with profibrotic mediators such as tissue plasminogen activator (tPA). These findings redefine STAT6 regulation, highlight an acetylation-phosphorylation checkpoint controlling fibrogenesis, and suggest that Kat5 enhancers or STAT6 acetylation mimetics may represent potential therapeutic strategies for chronic lung disease.