Journal Article

Tight junction dysfunction and cytoskeletal remodeling in Hirschsprung-associated enterocolitis: A decade of mechanistic insights and therapeutic prospects (Review)

Tang, Shao-Tao, Liu, Yuan, Li, Kang, Li, Lizhi, Li, Shuai, Wang, Chen, Zhang, Ling, Chen, Shan, Zhou, Ying, Wang, Yong, Yang, Dehua, Chi, Shuiqing

2026

Overview

Hirschsprung-associated enterocolitis (HAEC) represents a severe complication of Hirschsprung disease, characterized by intestinal barrier dysfunction and life-threatening inflammation. The present study systematically reviews the updated molecular mechanisms underlying HAEC pathogenesis, with particular focus on the tight junction (TJ) proteins claudin, occludin and zonula occludens protein 1 (ZO-1) and their interactions with the actin cytoskeleton. The present review demonstrates that dysregulation of claudin family members, particularly upregulation of pore-forming claudin-2 and downregulation of barrier-forming claudin-4, disrupts intestinal homeostasis. Occludin undergoes cytokine-mediated endocytosis through myosin light chain kinase (MLCK)/NF-κB signaling, while ZO-1 dysfunction impairs mechanical coupling between TJs and actin filaments. Furthermore, the present review identifies that inflammatory mediators, such as IL-1β, TNF-α and IFN-γ, trigger actin cytoskeleton remodeling via the cofilin phosphorylation cycle and the Rho-associated protein kinase/MLCK pathway, establishing a cycle of barrier breakdown. Importantly, the present review highlights the lipocalin 10/slingshot homologue 1/cofilin axis and TJ-cytoskeleton interactions as mechanistic targets for future intervention in HAEC treatment. These findings provide a comprehensive mechanistic framework for understanding HAEC pathogenesis and offer novel targets for clinical intervention.

• Publisher: D.A. Spandidos,Spandidos Publications UK Ltd
• Subject: Actin / Actin Cytoskeleton - metabolism / Amino acids / Animals / Cofilin / Cytokines / Cytoskeleton / Cytoskeleton - metabolism / Diarrhea / Endocytosis / Enterocolitis / Enterocolitis - etiology / Enterocolitis - metabolism / Enterocolitis - pathology / Enterocolitis - therapy / Filaments / Genotype & phenotype / Heparan sulfate / Hirschsprung disease / Hirschsprung Disease - complications / Hirschsprung Disease - metabolism / Hirschsprung Disease - pathology / Hirschsprung's disease / Hirschsprung-associated enterocolitis / Homeostasis / Humans / Inflammation / intestinal epithelial barrier / Intestine / Kinases / Lipocalin / Mechanical properties / Molecular modelling / Myosin-light-chain kinase / NF-κB protein / Pathogenesis / Pathogens / Permeability / Phosphorylation / Proteins / Signal Transduction / tight junction / Tight Junctions - metabolism / Tight Junctions - pathology / Tumor necrosis factor-α / Zonula occludens-1 protein / γ-Interferon