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Introduction <p>Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a type II acute-phase protein with anti-inflammatory and anti-apoptotic properties. This study investigated the role of ITIH4 in regulating Hippo signaling and alveolar epithelial type II cell (AECII) apoptosis during acute respiratory distress syndrome (ARDS)</p> Methods <p>A549 cells were used for ITIH4 knockdown, ITIH4 overexpression, and lipopolysaccharide (LPS) exposure following recombinant ITIH4 (rITIH4) treatment. The expressions of Hippo signaling components (YAP/TAZ), apoptotic markers (ATM, p53, caspase-3), and the senescence marker SIRT1 were examined. Next, C57BL/6JNarl and B6.Sftpc-CreERT2;Ai14(RCLtdT)-D mice were administered intratracheal LPS and daily intranasal rITIH4. Lung injury severity was assessed through H&amp;E staining with K-means clustering and immunofluorescence quantified ITIH4, caspase-3, and YAP expression in SPC⁺ cells from different lung regions</p> Results <p>The expression of YAP and TAZ decreased with ITIH4 knockdown in A549, whereas p-YAP and SIRT1 increased, and p-TAZ/TAZ decreased with ITIH4 overexpression. We also observed the expression of p-TAZ/TAZ and SIRT1 increased, while ATM and caspase-3 decreased in LPS-injured A549 following rITIH4 treatment. Furthermore, rITIH4 administration restored ITIH4 in SPC⁺ cells and reduced caspase-3 expression in LPS-induced ARDS mice. rITIH4 elevated YAP in SPC⁺ cells within damaged and severely injured lung regions on day 3; this upregulation was attenuated by day 7, suggesting spatiotemporal regulation of Hippo signaling activity during lung repair</p> Conclusion <p>rITIH4 mitigated LPS-induced lung injury by regulating YAP/TAZ activity and suppression of caspase-3 and ATM expression. The observed modulation of Hippo signaling and reduction of AECII apoptosis highlight ITIH4 as a therapeutic potential for ARDS.</p> Graphical Abstract <p></p>

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Role of ITIH4 in Modulating YAP/TAZ-Mediated Apoptosis of Type II Alveolar Epithelium during Acute Respiratory Distress Syndrome

  • 期刊论文

  • 发表日期：

    2026年2月25日

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  • Yu-Syuan Shih,
  • Xiao-Yue Chen,
  • Yi-Wei Lin,
  • Zih-An Liao,
  • Yi-Hsuan Liu,
  • Vincent Laiman,
  • Syue-Wei Peng,
  • Kazuhiro Ito,
  • Hsiao-Chi Chuang

摘要

Introduction

Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a type II acute-phase protein with anti-inflammatory and anti-apoptotic properties. This study investigated the role of ITIH4 in regulating Hippo signaling and alveolar epithelial type II cell (AECII) apoptosis during acute respiratory distress syndrome (ARDS)

Methods

A549 cells were used for ITIH4 knockdown, ITIH4 overexpression, and lipopolysaccharide (LPS) exposure following recombinant ITIH4 (rITIH4) treatment. The expressions of Hippo signaling components (YAP/TAZ), apoptotic markers (ATM, p53, caspase-3), and the senescence marker SIRT1 were examined. Next, C57BL/6JNarl and B6.Sftpc-CreERT2;Ai14(RCLtdT)-D mice were administered intratracheal LPS and daily intranasal rITIH4. Lung injury severity was assessed through H&E staining with K-means clustering and immunofluorescence quantified ITIH4, caspase-3, and YAP expression in SPC⁺ cells from different lung regions

Results

The expression of YAP and TAZ decreased with ITIH4 knockdown in A549, whereas p-YAP and SIRT1 increased, and p-TAZ/TAZ decreased with ITIH4 overexpression. We also observed the expression of p-TAZ/TAZ and SIRT1 increased, while ATM and caspase-3 decreased in LPS-injured A549 following rITIH4 treatment. Furthermore, rITIH4 administration restored ITIH4 in SPC⁺ cells and reduced caspase-3 expression in LPS-induced ARDS mice. rITIH4 elevated YAP in SPC⁺ cells within damaged and severely injured lung regions on day 3; this upregulation was attenuated by day 7, suggesting spatiotemporal regulation of Hippo signaling activity during lung repair

Conclusion

rITIH4 mitigated LPS-induced lung injury by regulating YAP/TAZ activity and suppression of caspase-3 and ATM expression. The observed modulation of Hippo signaling and reduction of AECII apoptosis highlight ITIH4 as a therapeutic potential for ARDS.

Graphical Abstract