Caveolin-1 has been reported to play an important role in the pathogenesis of acute respiratory distress syndrome (ARDS). This study was designed to identify Caveolin-l-interacting proteins to reveal the molecular mechanisms of ARDS. Yeast two-hybrid screening was performed using Caveolin-1 as the bait, and Axin-1 was identified as a binding partner for Caveolin-1. Co-immunoprecipitation demonstrated that the binding domains were located in the N-terminal region (1-100 aa) of Caveolin-1 and the C-terminal region (710-797 aa) of Axin-1. Caveolin-1 gene knockout or Axin-1 knockdown significantly decreased the levels of TNF-alpha and IL-6 in the supernatants of alveolar type I (AT-I) epithelial cells treated with LPS. Disrupting the interaction between Caveolin-1 and Axin-1 using CRISPR/Cas9 technology led to a significant increase in TNF-alpha and IL-6 from AT-I cells, along with a significant reduction in beta-catenin expression. In conclusion, Axin-1 functions as an adaptor of Caveolin-1 and affects the production of inflammatory cytokines in AT-I cells challenged with LPS via gamma-catenin-mediated negative regulation. (C) 2019 Elsevier Inc. All rights reserved.