2. Academic Validation
  3. PKM2-Driven Lactate Overproduction Triggers Endothelial-To-Mesenchymal Transition in Ischemic Flap via Mediating TWIST1 Lactylation

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

  • Adv Sci (Weinh). 2024 Dec;11(47):e2406184. doi: 10.1002/advs.202406184.
Yining Xu 1 2 3,  Xianhui Ma 1 2 3,  Weiyu Ni 4 5,  Lin Zheng 1 2 3,  Zhongnan Lin 1 2 3,  Yingying Lai 1 2 3,  Ningning Yang 1 2 3,  Zhanqiu Dai 1 2 3,  Teng Yao 4 5,  Zeyang Chen 1 2 3,  Lifeng Shen 4 5,  Haitao Wang 4 5,  Long Wang 1 2 3,  Yizheng Wu 4 5,  Weiyang Gao 1 2 3
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
  • 2 Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China.
  • 3 The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325027, China.
  • 4 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 5 Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310006, China.
PMID: 39474980 DOI: 10.1002/advs.202406184
Abstract

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

Keywords

Pyruvate kinase M2; endothelial‐to‐mesenchymal transition; lactate; lactylation; random‐pattern skin flap.

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