ABCG2 Upregulation Involving AKT/NF-κB Signaling Contributes to Intestinal Barrier Dysfunction in Inflammatory Bowel Disease

  • Dig Dis Sci. 2026 May 29. doi: 10.1007/s10620-026-10016-6.
Ping Shi  #  1  2 ,  Juan Deng  #  3 ,  Xiaomei Song  #  4 ,  Lianhua Tang  1  2 ,  Hong Guo  4 ,  Fei Yin  5  6
Affiliations
  • 1. Chongqing Key Laboratory of Target-Based Drug Discovery and Research, Chongqing University of Technology, Chongqing, 400054, People's Republic of China.
  • 2. College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, People's Republic of China.
  • 3. Chongqing Academy of Chinese Materia Medica, Chongqing University of Chinese Medicine, Chongqing, 400065, People's Republic of China.
  • 4. Department of Gastroenterology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, People's Republic of China.
  • 5. Chongqing Key Laboratory of Target-Based Drug Discovery and Research, Chongqing University of Technology, Chongqing, 400054, People's Republic of China. [email protected].
  • 6. College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 42213380 DOI: 10.1007/s10620-026-10016-6
Abstract

Background: Previous investigations demonstrated significant upregulation of ATP-binding cassette subfamily G member 2 (ABCG2) in renal, hepatic, colonic, and intestinal tissues within a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced murine model of Crohn's disease (CD). Nevertheless, the regulatory mechanisms governing ABCG2 expression within inflammatory microenvironments and its consequent impact on intestinal barrier integrity remain incompletely elucidated.

Aims: This study aimed to elucidate the signaling pathway responsible for ABCG2 upregulation under inflammatory conditions and to investigate the functional role of ABCG2 in intestinal barrier integrity both in vitro and in vivo.

Methods: Intestinal epithelial barrier integrity was evaluated by measuring transepithelial electrical resistance (TEER), paracellular permeability to fluorescein isothiocyanate (FITC)-dextran, and immunofluorescence/immunoblot analysis of tight junction proteins. Abcg2-/- mice were utilized to evaluate the contribution of ABCG2 to intestinal barrier homeostasis.

Results: ABCG2 expression was observed to be significantly elevated in lipopolysaccharide (LPS)-stimulated intestinal epithelial cells. This induction coincided with enhanced phosphorylation of Akt and P65. Pharmacological inhibition of Akt (LY294002) or NF-κB (BAY117082) attenuated the LPS-mediated upregulation of ABCG2. Functional assessments revealed that pharmacological inhibition of ABCG2 (using Ko143) or its genetic ablation enhanced intestinal barrier integrity. This was evidenced by increased TEER, reduced permeability to FITC-dextran, and restored expression of key tight junction proteins (ZO-1, occludin, and claudin-1) following LPS challenge. Specifically, Abcg2 knockout improved colon length, preserved mucosal architectural integrity, and diminished inflammatory cell infiltration in both dextran sulfate sodium (DSS)-UC and TNBS-induced CD models.

Conclusions: ABCG2 reprents a promising therapeutic target for inflammatory bowel disease (IBD), particularly in patient populations exhibiting dysregulated transporter activity or genetic variants influencing drug response.

Keywords
ATP-binding cassette subfamily G member 2 (ABCG2); Experimental colitis; Inflammatory bowel disease (IBD); Intestinal barrier; Tight junction proteins.
Products