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<p>Gut barrier dysfunction is a key feature of acute liver injury (ALI) and leads to systemic<!-- Query ID="Q1" Text="Please check article title if captured correctly." --> immune responses (SIRS). Our previous studies have demonstrated that knockout of osteopontin (OPN) modulates antimicrobial peptide expression and reduces intestinal flora, thereby ameliorating sepsis. In this study, we employed an acetaminophen (APAP)-induced hepatotoxicity model, the leading cause of acute liver failure (ALF) worldwide, to investigate the role of intestinal epithelial-derived OPN in gut barrier integrity during ALF. We found that intestinal epithelial-specific OPN knockout mice (<i>Opn</i><sup>△</sup><sup><i>IEC</i></sup>) exhibited significant protection against APAP-induced liver injury and reduced gut barrier leakage. Fecal transplantation<!-- Query ID="Q2" Text="Please confirm if the author names are presented accurately and in the correct sequence. Otherwise amend if necessary." --> experiments revealed that mice receiving feces from <i>Opn</i><sup>△</sup><sup><i>IEC</i></sup> mice showed increased resistance to APAP-induced liver injury and enhanced immune defense. Mechanistically, transcriptome analysis of the gut barrier indicated that OPN exacerbated gut barrier damage by inhibiting gut self-renewal via the JAK3/STAT4 signaling pathway. Epithelial-derived OPN may play a critical role in<!-- Query ID="Q3" Text="Please check if affiliations were captured and presented correctly." --> compromising gut barrier integrity and may be a target for suppressing inflammation and ameliorating ALI.</p> Graphical abstract <p></p>

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Deficiency of osteopontin in gut epithelial cells enhances intestinal integrity by promoting gut renewal through the JAK3/STAT4 pathway in acetaminophen (APAP)-induced acute liver injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月19日

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  • Chang Yu,
  • Yihan Qian,
  • Yuge Zhou,
  • Yali Sang,
  • Weifan Huang,
  • Limeng Yang,
  • Liyue Lu,
  • Xing Rong,
  • Hailong Wu,
  • Yanjun Shi,
  • Xiaoni Kong

摘要

Gut barrier dysfunction is a key feature of acute liver injury (ALI) and leads to systemic immune responses (SIRS). Our previous studies have demonstrated that knockout of osteopontin (OPN) modulates antimicrobial peptide expression and reduces intestinal flora, thereby ameliorating sepsis. In this study, we employed an acetaminophen (APAP)-induced hepatotoxicity model, the leading cause of acute liver failure (ALF) worldwide, to investigate the role of intestinal epithelial-derived OPN in gut barrier integrity during ALF. We found that intestinal epithelial-specific OPN knockout mice (Opn△IEC) exhibited significant protection against APAP-induced liver injury and reduced gut barrier leakage. Fecal transplantation experiments revealed that mice receiving feces from Opn△IEC mice showed increased resistance to APAP-induced liver injury and enhanced immune defense. Mechanistically, transcriptome analysis of the gut barrier indicated that OPN exacerbated gut barrier damage by inhibiting gut self-renewal via the JAK3/STAT4 signaling pathway. Epithelial-derived OPN may play a critical role in compromising gut barrier integrity and may be a target for suppressing inflammation and ameliorating ALI.

Graphical abstract