Balancing act: The dual role of claudin‐2 in disease

Claudin-2 (CLDN2), a tight junction protein, is predominantly found in leaky epithelial cell layers where it plays a pivotal role in forming paracellular pores necessary for the efficient transport of cations and water. Its abundance is intricately regulated by upstream signals, modulating its synthesis, transport, and localization to adapt to diverse environmental changes. Aberrant expression levels of CLDN2 are observed in numerous pathological conditions including cancer, inflammation, immune disorders, fibrosis, and kidney and biliary stones. Recent advances have uncovered the mechanisms by which the loss or restoration of CLDN2 affects functions such as epithelial barrier, cell proliferation, renewal, migration, invasion, and tissue regeneration. This exerts a dual-directional influence on the pathogenesis, perpetuation, and progression of diseases, indicating the potential to both accelerate and decelerate the course of disease evolution. Here, we discuss these nuanced bidirectional regulatory effects mediated by CLDN2, and how it may contribute to the progression or regression of disease when it becomes unbalanced.