Claudins As Signaling Hubs of Fibrosis, Autophagy, and Metabolism

Claudins were identified in 1998 as structural and functional components of tight junction (TJ) seals between adjacent epithelial cells. Since their identification, pharmaceutical research has mainly focused on junctional claudins. For example, permeation enhancers that modulate claudin-based TJ seals have been developed to enhance gastrointestinal, pulmonary, and epidermal absorption of drugs. Inflammation, a common feature of various diseases, is often accompanied by the disruption of claudin-based seals. Consequently, junctional claudin modulators have been developed for treating inflammatory diseases. In 2022, antibodies against non-junctional claudin-1 were produced, and these antibodies attenuated hepatic fibrosis by inhibiting a fibrotic signaling pathway that depends on non-junctional claudin-1. Claudin-targeted drug development has entered a new era, transitioning from the barrier function of TJ claudins to signaling hub-associated claudins. In this review, we discuss recent findings on claudins as drug targets in relation to fibrosis, autophagy, and metabolism, focusing specifically on their functions as signaling hubs.