Breathing life into fibrosis research: Precision-cut lung slices, organoids, and organs-on-chip as transformative models

Pulmonary fibrosis represents one of the most challenging frontiers in respiratory medicine, characterized by progressive scarring that ultimately leads to respiratory failure and death. Despite decades of research, therapeutic options remain frustratingly limited, with only three Food and Drug Administration (FDA)-approved agents that merely slow disease progression without reversing established fibrosis. This therapeutic impasse stems largely from the translational disconnect between traditional preclinical models and human disease complexity. Animal models fail to recapitulate the chronic, progressive nature of human fibrosis, while conventional cell culture systems cannot capture the intricate three-dimensional (3D) architecture and multicellular interactions that drive fibrotic remodeling. The emergence of new approach methodologies (NAMs) has catalyzed a paradigm shift in pulmonary fibrosis research, offering unprecedented opportunities to model human disease with greater fidelity. This review examines three revolutionary platforms that are reshaping our understanding of fibrotic mechanisms: precision-cut lung slices that preserve native tissue architecture, self-organizing lung organoids that enable patient-specific disease modeling, and microfluidic lung-on-chip systems that recreate physiological breathing mechanics. We critically evaluate the unique capabilities and inherent limitations of each technology, explore their applications in mechanistic studies and drug discovery, and discuss emerging hybrid approaches that promise to accelerate therapeutic development. By synthesizing current evidence and identifying future directions, this review provides a roadmap for leveraging these innovative technologies to finally break through the therapeutic ceiling in pulmonary fibrosis.