Scholarlink

Background <p>Endotoxemia causes pulmonary barrier disruption, endothelial dysfunction, and myeloid-mediated inflammatory responses leading to sepsis-associated acute lung injury. Histone deacetylase 6 (HDAC6) regulates cytoskeletal dynamics and inflammatory signaling; however, its cell-type-specific effects in inflammatory lung injury remain undetermined.</p> Methods <p>We conducted single-cell RNA sequencing in a mouse endotoxemia model to investigate the effects of HDAC6 inhibition on endothelial and macrophage responses. Key findings were confirmed using histology and bulk RNA sequencing studies.</p> Results <p>In endothelial cells, lipopolysaccharide induced inflammation and STAT pathway activation. HDAC6 inhibition with CAY10603 suppressed these changes, lowered inflammatory and apoptotic scores, and maintained endothelial cells toward earlier pseudotime states. Concurrently, HDAC6 inhibition via CAY10603 treatment restored angiogenesis-associated gene expression (<i>Acadl</i>, <i>Adrb2</i>, <i>Cd24a</i>, <i>Ecm1</i>, and <i>Ptgs1</i>). In macrophages, CAY10603 treatment suppressed lipopolysaccharide-induced interferon, inflammasome, and IL-6/JAK/STAT3 signatures and downregulated key gene expression (<i>Isg15</i>, <i>Ifit1/2</i>, <i>Lcn2</i>, <i>Txnip</i>, and <i>Irf1</i>), maintaining them in less activated states. These findings correlated with reduced alveolar congestion and leukocyte infiltration and suppressed inflammation signatures.</p> Conclusions <p>Selective HDAC6 inhibition suppresses endothelial activation and macrophage inflammatory programs while promoting angiogenic transcriptional programs, supporting further evaluation of HDAC6-targeted strategies for sepsis-associated lung injury.</p> Graphical Abstract <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

HDAC6 inhibition reprograms endothelial and macrophage responses to protect the lung in endotoxemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月5日

查看全文
  • Yanlei Li,
  • Yan Wang,
  • Wei Li,
  • Jinyan Yu

摘要

Background

Endotoxemia causes pulmonary barrier disruption, endothelial dysfunction, and myeloid-mediated inflammatory responses leading to sepsis-associated acute lung injury. Histone deacetylase 6 (HDAC6) regulates cytoskeletal dynamics and inflammatory signaling; however, its cell-type-specific effects in inflammatory lung injury remain undetermined.

Methods

We conducted single-cell RNA sequencing in a mouse endotoxemia model to investigate the effects of HDAC6 inhibition on endothelial and macrophage responses. Key findings were confirmed using histology and bulk RNA sequencing studies.

Results

In endothelial cells, lipopolysaccharide induced inflammation and STAT pathway activation. HDAC6 inhibition with CAY10603 suppressed these changes, lowered inflammatory and apoptotic scores, and maintained endothelial cells toward earlier pseudotime states. Concurrently, HDAC6 inhibition via CAY10603 treatment restored angiogenesis-associated gene expression (Acadl, Adrb2, Cd24a, Ecm1, and Ptgs1). In macrophages, CAY10603 treatment suppressed lipopolysaccharide-induced interferon, inflammasome, and IL-6/JAK/STAT3 signatures and downregulated key gene expression (Isg15, Ifit1/2, Lcn2, Txnip, and Irf1), maintaining them in less activated states. These findings correlated with reduced alveolar congestion and leukocyte infiltration and suppressed inflammation signatures.

Conclusions

Selective HDAC6 inhibition suppresses endothelial activation and macrophage inflammatory programs while promoting angiogenic transcriptional programs, supporting further evaluation of HDAC6-targeted strategies for sepsis-associated lung injury.

Graphical Abstract