AZD6738 Attenuates LPS-Induced Corneal Inflammation and Fibrosis by Modulating Macrophage Function and Polarization

This study aimed to evaluate the therapeutic potential of AZD6738, an ATR Inhibitor, in LPS-induced Bacterial keratitis (BK) by targeting macrophage function and polarization. A murine model of LPS-induced BK was established, with AZD6738 (100 µM) administered subconjunctivally and topically. Corneal opacity, edema, and inflammation were assessed using slit-lamp microscopy and histological analysis. Macrophage infiltration and fibrosis were evaluated via immunofluorescence, qPCR, and Western blotting. In vitro, RAW264.7 cells were treated with 2.5 µM AZD6738 to examine its effects on cell viability, oxidative stress, and inflammation-related gene expression. AZD6738 significantly reduced corneal opacity, thickness, and neovascularization in LPS-treated mice. It suppressed macrophage infiltration, collagen deposition, and pro-inflammatory cytokine expression. In RAW264.7 cells, AZD6738 induced cell death, elevated ROS production, and downregulated inflammatory markers. ATR inhibition mitigated NF-κB activation and modulated macrophage polarization, attenuating M1 pro-inflammatory responses. AZD6738 effectively alleviates LPS-induced corneal inflammation and fibrosis by regulating macrophage function and polarization via the NF-κB signaling pathway. ATR inhibition represents a promising therapeutic strategy for the treatment of corneal inflammation.

NF-κB signaling; AZD6738 (ceralasertib); Corneal inflammation and fibrosis; LPS-induced bacterial keratitis; Macrophage polarization.