GCN5-Mediated Lactylation of YY1 Promotes Diabetic Cardiomyopathy by Activating Twist1-Dependent EndMT

Endothelial-to-mesenchymal transition (EndMT) plays a pivotal role in fibroblast proliferation and cardiac fibrosis during diabetic cardiomyopathy (DCM) development, yet its underlying regulatory mechanisms remain unknown. The objective of this study is to investigate the role of general control non-repressed 5 protein (GCN5) and its mediated protein lactylation in regulating EndMT during DCM progression. We combined in vitro (high glucose (HG)-treated HUVECs) and in vivo (high-fat diet (HFD)/streptozotocin (STZ)-induced DCM mice) models with endothelial-specific GCN5-knockout mice. Pathological changes and fibrosis in cardiac tissue were assessed using HE staining and Masson staining, respectively. Cell migration was determined using wound healing and Transwell assays. Co-IP assay was employed to detect YY1 lactylation, as well as the interaction between YY1 and GCN5. ChIP and dual-luciferase reporter assays were employed to analyze the binding relationship between YY1 and the Twist1 promoter. GCN5 was upregulated in diabetic hearts and endothelial cells, and its knockdown reduced Twist1-dependent EndMT in HG-treated HUVECs. Mechanistically, GCN5 catalyzed YY1 lactylation at K203, which enhanced YY1 phosphorylation at Thr398, activating Twist1 transcription. GCN5 knockdown reversed the promoting effect of wildtype YY1 overexpression on HG-induced EndMT but didn't affect the effect of mutant YY1 overexpression on EndMT. Endothelial-specific GCN5 deletion reversed HFD/STZ-induced cardiac dysfunction and fibrosis in mice by inhibiting Twist1-dependent EndMT. GCN5 enhanced Twist1 transcription by promoting lactylation of YY1 at K203 and its phosphorylation at Thr398, thereby increasing EndMT in DCM. This GCN5-YY1-Twist1 axis may offer novel therapeutic targets for DCM management.