PKM2‐Driven Lactate Overproduction Triggers Endothelial‐To‐Mesenchymal Transition in Ischemic Flap via Mediating TWIST1 Lactylation

• DOI: 10.1002/advs.202406184
• Publication Date: 2024-10-30T15:58:12Z
• Authors: Yining Xu; Xianhui Ma; Weiyu Ni; Lin Zheng; Zhongnan Lin; Yingying Lai; Ningning Yang; Zhanqiu Dai; Teng Yao; Zeyang Chen; Lifeng Shen; Haitao Wang; Long Wang; Yizheng Wu; Weiyang Gao
• Keywords: random‐pattern skin flap; lactate; Science; Q; lactylation; endothelial‐to‐mesenchymal transition; Pyruvate kinase M2; Research Article

Abstract The accumulation of lactate is a rising risk factor for patients after flap transplantation. Endothelial‐to‐mesenchymal transition (EndoMT) plays critical role in skin fibrosis. Nevertheless, whether overproduction directly contributes to necrosis and its mechanism remain unknown. current study reveals that mice exhibit enhanced PKM2 fibrotic response. Endothelial‐specific deletion attenuates ameliorates fibrosis mice. Administration or overexpressing promotes dysfunction endothelial cells stimulates mesenchymal‐like phenotype following hypoxia. Mechanistically, glycolytic‐lactate induces correlation between Twist1 p300/CBP, leading lactylation lysine 150 (K150la). increase K150la phosphorylation nuclear translocation further regulates the transcription TGFB1 , hence inducing phenotype. Genetically endothelial‐specific diminishes lactylation, then EndoMT‐associated ischemia. serum levels transplantation are elevated predictive value prognosis. This findings suggested novel PKM2‐derived mediating exacerbates Inhibition reduces response might become potential therapeutic strategy