Scholarlink

<p>Dysfunction of vascular endothelial cells is recognized as a critical driver in pulmonary vascular remodeling of pulmonary hypertension (PH). Although interleukin-6 (IL-6) has been firmly established as an indispensable factor leading to pulmonary vascular remodeling, its downstream molecular mechanisms remain incompletely elucidated. Here, we discover that ubiquitin-specific protease 2a (USP2a) is upregulated in lung tissues of PH patients and preclinical PH models, and in IL-6-stimulated endothelial cells. Both the endothelial cell-specific <i>Usp2a</i> genetic deletion and the pharmacological inhibition of USP2a with the inhibitor ML364 alleviate experimental PH manifestations. Mechanistically, USP2a attenuates the degradation of methyltransferase-like 16 (METTL16) by deubiquitination. Notably, METTL16 reciprocally enhances USP2a expression via interactions with eIF3a and eIF3b in a methyltransferase activity-independent manner, establishing a self-reinforcing USP2a-METTL16 regulatory loop. Subsequent investigations reveal that METTL16 enhances N6-methyladenosine (m<sup>6</sup>A)-mediated <i>IL-6 receptor</i> (<i>IL-6R</i>) mRNA stabilization, thereby promoting the expression of IL-6R. This study demonstrates that endothelial USP2a-METTL16 loop potentiates IL-6 signaling via IL-6R and represents a promising therapeutic target for PH.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Endothelial USP2a-METTL16 loop potentiates IL-6 signaling via m6A-mediated IL-6R stabilization in pulmonary vascular remodeling

  • 期刊论文

  • 发表日期：

    2026年4月25日

查看全文
  • Hanqing Zhu,
  • Ping Yuan,
  • Xiangyang Wu,
  • Yuxia Huang,
  • Wentian Zhang,
  • Xingxing Sun,
  • Jianhua Xu,
  • Tianran Zhou,
  • Junfang Xu,
  • Li Chen,
  • Wenlan Yang,
  • Jinming Liu,
  • Haipeng Liu,
  • Fenghou Gao,
  • Jian Guo

摘要

Dysfunction of vascular endothelial cells is recognized as a critical driver in pulmonary vascular remodeling of pulmonary hypertension (PH). Although interleukin-6 (IL-6) has been firmly established as an indispensable factor leading to pulmonary vascular remodeling, its downstream molecular mechanisms remain incompletely elucidated. Here, we discover that ubiquitin-specific protease 2a (USP2a) is upregulated in lung tissues of PH patients and preclinical PH models, and in IL-6-stimulated endothelial cells. Both the endothelial cell-specific Usp2a genetic deletion and the pharmacological inhibition of USP2a with the inhibitor ML364 alleviate experimental PH manifestations. Mechanistically, USP2a attenuates the degradation of methyltransferase-like 16 (METTL16) by deubiquitination. Notably, METTL16 reciprocally enhances USP2a expression via interactions with eIF3a and eIF3b in a methyltransferase activity-independent manner, establishing a self-reinforcing USP2a-METTL16 regulatory loop. Subsequent investigations reveal that METTL16 enhances N6-methyladenosine (m6A)-mediated IL-6 receptor (IL-6R) mRNA stabilization, thereby promoting the expression of IL-6R. This study demonstrates that endothelial USP2a-METTL16 loop potentiates IL-6 signaling via IL-6R and represents a promising therapeutic target for PH.