ZBTB4 Deficiency Exacerbates DSS-Induced Colitis Through Activating NF-κB Pathway.

Area of Science:

• Gastroenterology
• Molecular Biology
• Immunology

Background:

• Inflammatory bowel diseases (IBD), including ulcerative colitis (UC), are chronic conditions with limited treatments.
• The role of the zinc-finger transcription factor ZBTB4 in UC pathogenesis is currently unknown.
• ZBTB4 is known for its involvement in cancer initiation and progression.

Purpose of the Study:

• To investigate the role of ZBTB4 in dextran sulfate sodium (DSS)-induced colitis, a model for UC.
• To identify potential therapeutic strategies targeting ZBTB4 for UC treatment.

Main Methods:

• Utilized a mouse model of DSS-induced colitis (C57BL/6J male mice) with wild-type and ZBTB4-deficient genotypes.
• Performed RNA sequencing (RNA-seq) to analyze gene expression changes in ZBTB4-deficient mice.
• Investigated the involvement of the NF-κB pathway and tested NF-κB inhibition using JSH-23.
• Conducted drug screening to identify compounds that modulate ZBTB4 expression, followed by in vivo validation with handelin.

Main Results:

• ZBTB4 deficiency significantly exacerbated DSS-induced colitis, leading to increased weight loss, colon shortening, and proinflammatory cytokine production.
• RNA-seq revealed that ZBTB4 deficiency upregulates Serpine1 expression and activates the NF-κB pathway.
• Inhibition of NF-κB by JSH-23 ameliorated the effects of ZBTB4 deficiency in the colitis model.
• The natural compound handelin was identified as a ZBTB4 enhancer and demonstrated therapeutic effects in wild-type mice with colitis, but not in ZBTB4 knockout mice.

Conclusions:

• ZBTB4 plays a protective role in the pathogenesis of ulcerative colitis.
• ZBTB4 deficiency exacerbates colitis through enhanced Serpine1 expression and NF-κB pathway activation.
• ZBTB4 agonists, such as handelin, represent a promising novel therapeutic strategy for ulcerative colitis treatment.