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

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.