A 3D multi-omics atlas of human lung fibrosis

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Introduction: Human lung fibrosis is a progressive and fatal disease marked by spatially heterogeneous scarring, yet the three-dimensional (3D) tissue-scale microenvironments in which fibrosis develops remain poorly defined. Conventional transcriptomic studies lack 3D architectural context, while imaging alone cannot reveal molecular change. Aims and objectives: To generate a 3D multi-omics atlas integrating lung microstructure with spatial gene and protein expression in human fibrosis. Methods: High-resolution micro-computed tomography (µCT) was integrated with spatial transcriptomic and proteomic profiling of diagnostic fibrotic and control lung tissue. Molecular data were digitally co-registered within the µCT volume, enabling visualisation of gene and protein expression within the 3D microarchitecture and spatial association with local structural metrics such as tissue density and vascular proximity. Results: Integrated 3D analysis revealed marked structural heterogeneity in fibrotic tissue, with increased local density, altered airway and vascular topology, and loss of normal alveolar geometry. Spatial transcriptomic clustering resolved discrete anatomical compartments, segregating fibrotic from control regions and defining alveolar, vascular, airway and fibroblast-focus domains. Integration of 3D µCT-derived metrics with molecular expression patterns revealed coordinated remodelling of epithelial, stromal and vascular programmes, defining distinct molecular–architectural niches within the fibrotic lung. Conclusions: We have established a 3D multi-omics atlas of human lung fibrogenesis, enabling high-resolution mapping of molecular–structural relationships and providing a framework to interrogate mechanisms and benchmark translational models.

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