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Objective <p>This study aims to elucidate the molecular mechanism by which F-box and WD repeat domain-containing 11 (FBXW11) promotes the progression of acute pancreatitis (AP) through ubiquitination-mediated degradation of Hypermethylated in Cancer 1 (HIC1), thereby enhancing Interferon Regulatory Factor 1 (IRF1) transcription.</p> Methods <p>A murine model of AP was generated by intraperitoneal cerulein administration, after which pancreatic tissues were harvested for RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) were screened, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Potential key regulators were identified using least absolute shrinkage and selection operator (LASSO) regression and random forest algorithms. Co-immunoprecipitation (Co-IP), ubiquitination, and chromatin immunoprecipitation (ChIP) assays were used to verify protein interactions and regulatory effects among FBXW11, HIC1, and IRF1. The impact of the FBXW11/HIC1 axis on AP-specific cellular phenotypes was assessed using qPCR, Western blot, immunofluorescence, CCK-8, Enzyme-Linked Immunosorbent Assay (ELISA), and flow cytometry. Finally, the role of the FBXW11/HIC1/IRF1 axis in AP was validated in vivo using a mouse model.</p> Results <p>RNA-seq identified 3489 DEGs significantly associated with immune regulation and ferroptosis pathways. FBXW11 emerged as a central regulator that promotes HIC1 ubiquitination and degradation, thereby releasing IRF1 from transcriptional suppression. Silencing of FBXW11 or overexpression of HIC1 markedly decreased inflammatory cytokines (IL-6, TNF-α, and IL-1β) and reduced cellular apoptosis. In vivo experiments showed that inhibiting FBXW11 expression significantly alleviated AP symptoms in mice, with marked reductions in pancreatic tissue damage and inflammatory response.</p> Conclusion <p>FBXW11 promotes the progression of AP by enhancing IRF1 transcription through the ubiquitination-mediated degradation of HIC1. Inhibition of FBXW11 or HIC1 effectively reduces the production of inflammatory cytokines and decreases cell apoptosis, thereby alleviating the symptoms of AP.</p>

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Mechanistic Investigation of FBXW11-Mediated Ubiquitination and Degradation of HIC1 in Regulating IRF1 Transcription and Accelerating Acute Pancreatitis Progression

  • 期刊论文

  • 发表日期：

    2025年11月25日

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  • Hai Jiang,
  • Jia Liu,
  • Junjie Tao,
  • Huaisheng Zhang,
  • Qi Song,
  • Heng Zhu,
  • Qiliang Li,
  • Zhipeng Xu,
  • Lei Li,
  • Yiping Mou

摘要

Objective

This study aims to elucidate the molecular mechanism by which F-box and WD repeat domain-containing 11 (FBXW11) promotes the progression of acute pancreatitis (AP) through ubiquitination-mediated degradation of Hypermethylated in Cancer 1 (HIC1), thereby enhancing Interferon Regulatory Factor 1 (IRF1) transcription.

Methods

A murine model of AP was generated by intraperitoneal cerulein administration, after which pancreatic tissues were harvested for RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) were screened, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Potential key regulators were identified using least absolute shrinkage and selection operator (LASSO) regression and random forest algorithms. Co-immunoprecipitation (Co-IP), ubiquitination, and chromatin immunoprecipitation (ChIP) assays were used to verify protein interactions and regulatory effects among FBXW11, HIC1, and IRF1. The impact of the FBXW11/HIC1 axis on AP-specific cellular phenotypes was assessed using qPCR, Western blot, immunofluorescence, CCK-8, Enzyme-Linked Immunosorbent Assay (ELISA), and flow cytometry. Finally, the role of the FBXW11/HIC1/IRF1 axis in AP was validated in vivo using a mouse model.

Results

RNA-seq identified 3489 DEGs significantly associated with immune regulation and ferroptosis pathways. FBXW11 emerged as a central regulator that promotes HIC1 ubiquitination and degradation, thereby releasing IRF1 from transcriptional suppression. Silencing of FBXW11 or overexpression of HIC1 markedly decreased inflammatory cytokines (IL-6, TNF-α, and IL-1β) and reduced cellular apoptosis. In vivo experiments showed that inhibiting FBXW11 expression significantly alleviated AP symptoms in mice, with marked reductions in pancreatic tissue damage and inflammatory response.

Conclusion

FBXW11 promotes the progression of AP by enhancing IRF1 transcription through the ubiquitination-mediated degradation of HIC1. Inhibition of FBXW11 or HIC1 effectively reduces the production of inflammatory cytokines and decreases cell apoptosis, thereby alleviating the symptoms of AP.