<p>Post-infectious pulmonary fibrosis remains difficult to prevent due to limited mechanistic understanding and the lack of human-relevant models. We engineered an immune-integrated lung-on-a-chip incorporating endothelial cells, fibroblasts, and macrophages to dissect early fibrotic signaling. Intravascular exposure to thymocyte selection-associated high mobility group box protein (TOX), a T cell–derived factor elevated after severe infection, impaired endothelial barrier function, upregulated intercellular adhesion molecule-1 (ICAM-1), and, through macrophages, induced fibroblast activation with increased α-smooth muscle actin (α-SMA), fibronectin, and extracellular matrix (ECM) remodeling. Pre-treatment with a receptor for advanced glycation end products (RAGE)-blocking antibody preserved barrier integrity and suppressed macrophage activation, fibroblast expansion, and collagen bundling. Similar protective effects were observed in a mouse model of TOX-induced fibrosis, where RAGE blockade improved survival and reduced collagen deposition. Analysis of profibrotic mediators revealed a conserved TOX–RAGE–macrophage signature across the chip model, mouse lungs, and patient bronchoalveolar lavage fluid (BALF) samples. These results identify TOX–RAGE signaling as a driver of post-infectious fibrotic remodeling and establish RAGE blockade as a potential preventive strategy.</p> Graphical abstract <p></p>