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<p>Caspase 6 is a pivotal executioner caspase involved in cell death; however, its role in inflammatory bowel disease (IBD) remains incompletely understood. Levels of cleaved caspase 6 were quantified in colonic tissues from IBD patients, and an IBD mouse model was established via DSS induction, incorporating both systemic (<i>Casp6</i> KO) and IEC-specific knockout (<i>Casp6</i> cKO) strategies. Single-cell RNA sequencing (scRNA-seq) revealed that <i>Casp6</i> KO enhanced necroptosis in IECs, reducing intestinal endocrine cells and damaging intestinal stem cells. Both in vivo and in vitro studies confirmed that caspase 6 deficiency activates the necroptosis pathway by upregulating RIPK1 in IECs and impairs macrophage bacterial clearance. Importantly, <i>Casp6</i> KO reduces bactericidal activity in a cathepsin L (CTSL)-dependent manner. These findings demonstrate that preserving caspase 6 activity is essential for necroptosis prevention and effective bacterial clearance, providing new insights for future IBD therapies.</p><p></p>

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Caspase 6 deficiency exacerbates inflammatory bowel disease via enterocyte necroptosis and bacterial translocation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月13日

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  • Qiong Liu,
  • Jun He,
  • Lixin Liu,
  • Leping Yang,
  • Xiaoyan Qi,
  • Zuxing Wei,
  • Xuyang Hou,
  • Dekun Liu,
  • Yimiao Cheng,
  • Ganglei Liu,
  • Yanwen Zheng,
  • Kuijie Liu

摘要

Caspase 6 is a pivotal executioner caspase involved in cell death; however, its role in inflammatory bowel disease (IBD) remains incompletely understood. Levels of cleaved caspase 6 were quantified in colonic tissues from IBD patients, and an IBD mouse model was established via DSS induction, incorporating both systemic (Casp6 KO) and IEC-specific knockout (Casp6 cKO) strategies. Single-cell RNA sequencing (scRNA-seq) revealed that Casp6 KO enhanced necroptosis in IECs, reducing intestinal endocrine cells and damaging intestinal stem cells. Both in vivo and in vitro studies confirmed that caspase 6 deficiency activates the necroptosis pathway by upregulating RIPK1 in IECs and impairs macrophage bacterial clearance. Importantly, Casp6 KO reduces bactericidal activity in a cathepsin L (CTSL)-dependent manner. These findings demonstrate that preserving caspase 6 activity is essential for necroptosis prevention and effective bacterial clearance, providing new insights for future IBD therapies.