Alveolar epithelial barrier disruption by FKBP5-mediated necroptosis aggravates lung injury.

Abstract

Alveolar epithelial barrier damage is a key pathological feature of acute respiratory distress syndrome (ARDS). The glycocalyx and tight junctions are essential for maintaining epithelial barrier function, and their disruption exacerbates pulmonary edema. Although FK506-binding protein 51 (FKBP5) regulates inflammatory responses, its mechanistic role in ARDS remains unclear. Here, we show that FKBP5 levels in bronchoalveolar lavage fluid from patients with sepsis-associated ARDS are significantly elevated and positively correlated with disease severity. In a lipopolysaccharide (LPS)-induced ARDS mouse model, Fkbp5^-/- markedly attenuated lung inflammatory injury and reduced damage to the epithelial glycocalyx and tight junctions. Transcriptomic analysis revealed that FKBP5 regulates inflammatory responses through the necroptosis pathway. Both in vivo and in vitro experiments further confirmed that genetic deletion or knockdown of FKBP5 suppresses necroptosis activation, reduces NF-κB signaling, and restores glycocalyx and tight junction integrity. Mechanistically, necroptosis-driven NF-κB activation promotes excessive cytokine production, which in turn damages the epithelial glycocalyx and tight junctions. These findings identify FKBP5 as a potential therapeutic target in ARDS and redefine the alveolar epithelium as an active contributor to the inflammatory microenvironment.