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<p>Hypoxia-related pulmonary arterial hypertension (PAH) remains poorly managed by current therapies. Metabolic dysregulation, particularly glycolysis, plays a key role in PAH pathogenesis. This study investigated YWHAZ’s role in PAH using hypoxia-induced pulmonary arterial endothelial cells (PAECs) and a hypoxia/SU5416-induced PAH rat model. Silencing YWHAZ inhibited PAEC proliferation, migration, and glycolysis, while improving right ventricular function and reducing pulmonary vascular remodeling. Mechanistically, YWHAZ stabilized HIF-1α, which transcriptionally activated LDHA, a critical glycolytic enzyme. HIF-1α agonist treatment reversed YWHAZ silencing effects, confirming the YWHAZ/HIF-1α/LDHA axis. These findings highlight YWHAZ as a potential therapeutic target for metabolic intervention in PAH.</p>

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YWHAZ-mediated metabolic reprogramming via HIF1A/LDHA signaling promotes pulmonary arterial remodelling

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月5日

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  • Zhong-Yuan Meng,
  • Chuang-Hong Lu,
  • Juan Liao,
  • Sen-Hu Tang,
  • Jing Li,
  • Xiao-Li Ma,
  • Yue Qin,
  • Chao-Yong Zhang,
  • Yao-Shi Hu,
  • De-Xin Chen,
  • Xing Chen,
  • Yan Deng,
  • Feng Huang,
  • Zhi-Yu Zeng

摘要

Hypoxia-related pulmonary arterial hypertension (PAH) remains poorly managed by current therapies. Metabolic dysregulation, particularly glycolysis, plays a key role in PAH pathogenesis. This study investigated YWHAZ’s role in PAH using hypoxia-induced pulmonary arterial endothelial cells (PAECs) and a hypoxia/SU5416-induced PAH rat model. Silencing YWHAZ inhibited PAEC proliferation, migration, and glycolysis, while improving right ventricular function and reducing pulmonary vascular remodeling. Mechanistically, YWHAZ stabilized HIF-1α, which transcriptionally activated LDHA, a critical glycolytic enzyme. HIF-1α agonist treatment reversed YWHAZ silencing effects, confirming the YWHAZ/HIF-1α/LDHA axis. These findings highlight YWHAZ as a potential therapeutic target for metabolic intervention in PAH.