2. Academic Validation
  3. Endothelial Hippo pathway regulates the neutrophil niche and lung fibrosis

Endothelial Hippo pathway regulates the neutrophil niche and lung fibrosis

  • Pharmacol Res. 2026 May:227:108169. doi: 10.1016/j.phrs.2026.108169.
Chuan Wu 1,  Xiangqi Chen 1,  Jingyue Zhou 1,  Han Wang 1,  Xiaojuan Huang 1,  Xiaoqiang Tang 2,  Zhongwei Cao 3,  Bi-Sen Ding 4
Affiliations

Affiliations

  • 1 Key Lab of Birth Defects and Related Diseases of Women and Children of MOE, State Key Lab of Biotherapy, State Key Laboratory of Respiratory Health and Multimorbidity, West China School of Basic Medical Sciences & Forensic Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.
  • 2 Key Lab of Birth Defects and Related Diseases of Women and Children of MOE, State Key Lab of Biotherapy, State Key Laboratory of Respiratory Health and Multimorbidity, West China School of Basic Medical Sciences & Forensic Medicine, West China Second University Hospital, Sichuan University, Chengdu, China. Electronic address: [email protected].
  • 3 Key Lab of Birth Defects and Related Diseases of Women and Children of MOE, State Key Lab of Biotherapy, State Key Laboratory of Respiratory Health and Multimorbidity, West China School of Basic Medical Sciences & Forensic Medicine, West China Second University Hospital, Sichuan University, Chengdu, China. Electronic address: [email protected].
  • 4 Key Lab of Birth Defects and Related Diseases of Women and Children of MOE, State Key Lab of Biotherapy, State Key Laboratory of Respiratory Health and Multimorbidity, West China School of Basic Medical Sciences & Forensic Medicine, West China Second University Hospital, Sichuan University, Chengdu, China. Electronic address: [email protected].
PMID: 41871675 DOI: 10.1016/j.phrs.2026.108169
Abstract

Lung fibrosis is a severe disease with limited therapeutic options. The vascular niche is critical for lung function and fibrotic diseases, but the mechanisms by which endothelial cells (ECs) are regulated during lung injury and fibrosis remain largely unknown. As a critical regulatory pathway in lung development, regeneration, and fibrosis, the role of Hippo/YAP1 in the endothelial niche remains elusive. Here, we provide evidence that endothelial Hippo facilitates lung fibrosis via regulating the neutrophil niche. The YAP1 is activated in ECs of fibrotic lungs in mice and humans. Activating YAP1 via depleting the upstream repressor SAV1 in ECs promotes bleomycin-induced lung fibrosis, while endothelial YAP1 deficiency reverses lung fibrosis. Mechanism study reveals that endothelial YAP1 regulates the expression of CXCL1, which recruits CXCR2+ neutrophil in injured lungs. Blocking neutrophil recruitment via CXCR2 Antagonist reduces lung fibrosis and blocks the effects of endothelial YAP1 activation. Therapeutically, inhibition of YAP1 with verteporfin reduces endothelial CXCL1 expression, neutrophil recruitment and lung fibrosis. Collectively, these findings demonstrate the roles of Hippo/YAP1 in regulating endothelial-neutrophil niche to participate in lung fibrosis.

Keywords

CXCL1; Endothelial cell; Hippo/YAP1; Lung fibrosis; Neutrophil.

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