Abstract
Chronic lung allograft dysfunction (CLAD) limits long-term lung graft survival, yet its specific gene expression profiles remain unclear. We performed comprehensive spatial transcriptomic analyses of human lungs from CLAD patients, non-CLAD transplant recipients, and non-transplanted controls. In CLAD, AP-1 target genes, including JUNB and FOS, were significantly upregulated in both the epithelium and endothelium, whereas anti-fibrotic genes such as A2M and surfactant proteins (SFTPA1,2) were upregulated in non-CLAD. The lymphocyte population in CLAD was predominantly composed of T cells, with elevated JAK3-IL7R signaling. TNF and IL-17 signaling pathways were commonly activated in both the epithelium and endothelium, with JUNB and FOS serving as central hubs within pro-inflammatory, pro-fibrotic gene networks. These findings suggest that coordinated AP-1 activation and shared inflammatory and fibrotic signaling across epithelial and endothelial compartments may drive CLAD. Our results highlight the transcriptionally active roles of both compartments and provide new mechanistic insights into CLAD pathogenesis.