Nintedanib Alleviates Experimental Colitis by Inhibiting CEBPB/PCK1 and CEBPB/EFNA1 Pathways

Area of Science:

• Genomics and Molecular Biology
• Immunology and Inflammation
• Pharmacology and Drug Discovery

Background:

• Super-enhancers, clusters of active enhancers, are increasingly recognized for their role in gene regulation.
• Understanding super-enhancer-driven gene expression is crucial for elucidating disease mechanisms, particularly in inflammatory conditions like IBD.
• Identifying specific pathogenic genes regulated by super-enhancers can reveal novel therapeutic targets.

Purpose of the Study:

• To investigate super-enhancer-driven pathogenic genes in inflammatory bowel disease (IBD).
• To screen for potential therapeutic drugs targeting these identified genes.
• To explore the role of CEBPB, PCK1, and EFNA1 in colitis and their regulation by super-enhancers.

Main Methods:

• Analysis of differentially expressed genes in colitis patients from the GEO database.
• Super-enhancer-associated database analysis to identify regulatory elements.
• Gene silencing experiments (CEBPB) and drug treatment assays (in vitro and in vivo models).
• Assessment of epithelial barrier protein expression and gut microbiota composition.

Main Results:

• PCK1 and EFNA1 were identified as pathogenic super-enhancer-driven genes in colitis, co-regulated by transcription factor CEBPB via two specific super-enhancers.
• Silencing CEBPB inhibited PCK1 and EFNA1 expression and restored epithelial barrier proteins.
• Nintedanib significantly inhibited CEBPB, PCK1, and EFNA1 expression in vitro and alleviated DSS-induced colitis in mice, improving gut microbiota.

Conclusions:

• PCK1 and EFNA1 are highly expressed in colitis and regulated by CEBPB through super-enhancers.
• Nintedanib demonstrates therapeutic potential for IBD by targeting the CEBPB/PCK1 and CEBPB/EFNA1 pathways.
• Super-enhancers represent a promising avenue for exploring colitis pathogenesis and developing new treatments.