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<p>To elucidate the role and regulatory mechanisms of macrophage-derived cystatin C (CST3) in Crohn’s disease (CD), focusing on colonic inflammation, macrophage–epithelial interactions, and barrier dysfunction. Colonic samples from CD patients, including inflamed and non-inflamed regions, were subjected to scRNA-seq. In vitro macrophage–epithelial co-culture models and untargeted metabolomics were employed, and the findings were validated using macrophage-specific CST3 knockout (KO) and overexpression mice under TNBS-induced and IL-10 KO colitis conditions. Mechanistic investigations included Co-IP, ChIP-qPCR, ubiquitination assays, rescue experiments, and functional analyses of efferocytosis, macrophage polarization, and barrier integrity. CST3 expression was considerably reduced in macrophages from inflamed CD tissues through suppressor of SMAD5-dependent transcriptional repression and MYCBP2-mediated K48-linked ubiquitination and degradation. Loss of CST3 impaired efferocytosis and M2 polarization by inhibiting the ACVR1C/TGF-β/SMAD pathway. CST3 deficiency also disrupted intestinal epithelial proliferation, compromised barrier function, and increased apoptosis via enhanced NAMPT-INSR signaling and accumulation of the inflammatory cytokines. In mice, macrophage-specific CST3 deletion exacerbated colitis, whereas its overexpression alleviated inflammation and restored epithelial integrity. These findings establish macrophage CST3 as a key regulator of immune–metabolic–epithelial crosstalk in CD, and indicate that restoring CST3 function or targeting its regulatory axis may represent a novel therapeutic strategy for CD.</p>

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Transcriptional and ubiquitinative suppression of macrophage CST3 disrupts colonic homeostasis through defective efferocytosis

  • 期刊论文

  • 发表日期：

    2026年5月5日

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  • Honggang Wang,
  • Chenyang Jiao,
  • Hailin Xing,
  • Chao Cheng,
  • Shaoqi Cheng,
  • Wenliang Jiang,
  • Ziwei Xu,
  • Jianbo Yang,
  • Jing Sun,
  • Jie Zhao

摘要

To elucidate the role and regulatory mechanisms of macrophage-derived cystatin C (CST3) in Crohn’s disease (CD), focusing on colonic inflammation, macrophage–epithelial interactions, and barrier dysfunction. Colonic samples from CD patients, including inflamed and non-inflamed regions, were subjected to scRNA-seq. In vitro macrophage–epithelial co-culture models and untargeted metabolomics were employed, and the findings were validated using macrophage-specific CST3 knockout (KO) and overexpression mice under TNBS-induced and IL-10 KO colitis conditions. Mechanistic investigations included Co-IP, ChIP-qPCR, ubiquitination assays, rescue experiments, and functional analyses of efferocytosis, macrophage polarization, and barrier integrity. CST3 expression was considerably reduced in macrophages from inflamed CD tissues through suppressor of SMAD5-dependent transcriptional repression and MYCBP2-mediated K48-linked ubiquitination and degradation. Loss of CST3 impaired efferocytosis and M2 polarization by inhibiting the ACVR1C/TGF-β/SMAD pathway. CST3 deficiency also disrupted intestinal epithelial proliferation, compromised barrier function, and increased apoptosis via enhanced NAMPT-INSR signaling and accumulation of the inflammatory cytokines. In mice, macrophage-specific CST3 deletion exacerbated colitis, whereas its overexpression alleviated inflammation and restored epithelial integrity. These findings establish macrophage CST3 as a key regulator of immune–metabolic–epithelial crosstalk in CD, and indicate that restoring CST3 function or targeting its regulatory axis may represent a novel therapeutic strategy for CD.