Beyond scarring: a next-generation vision for pulmonary fibrosis management

Interstitial pulmonary fibrosis remains a progressive, fatal lung disease with a median survival of approximately 4-5 years in contemporary registry data and limited therapies that slow but do not halt or reverse fibrosis. A fundamental reconceptualization of IPF from a static scar to a dynamic, cellularly heterogeneous ecosystem is emerging, driven by recent technological breakthroughs.

This review synthesizes and critically evaluates peer-reviewed literature and clinical trial data from 2015 to 2025. We integrate findings from single-cell and spatial transcriptomics, artificial intelligence (AI)-enhanced imaging, and clinical studies on regenerative and targeted therapies to construct a new framework for IPF management.

Single-cell atlases have revealed unprecedented pathological cellular states, including epithelial-mesenchymal hybrid cells and specialized fibroblast niches (HAS1hi, PLIN2⁺ subsets), whose lineage relationships remain incompletely defined. Expanded SPP1hi profibrotic macrophages have been identified as key orchestrators of progressive remodeling, demonstrating that specific immune populations rather than broad inflammation actively drive fibrosis. Concurrently, AI shows strong diagnostic performance for classifying fibrotic lung disease and early promise for predicting progression, though prospective validation remains ongoing. Therapeutically, the paradigm is shifting from antifibrotic containment to regenerative restoration, although currently approved agents provide only modest individual benefit and are frequently constrained by tolerability issues. Early clinical data on senolytics (dasatinib/quercetin), high-dose mesenchymal stem cells, and acellular approaches (lung spheroid cell exosomes) show promise in modifying disease biology and improving functional outcomes. Future development will require robust target engagement biomarkers and innovative trial designs informed by lessons from recent negative phase III studies. Integration of these advances through multi-omics endotyping and digital twin technology paves the way for personalized precision medicine.

The convergence of single-cell biology, computational medicine, and regenerative strategies establishes a new "Beyond Scarring" paradigm. This framework moves the therapeutic goal beyond deceleration of fibrosis toward active lung repair and functional restoration. Future IPF management will require interdisciplinary integration, biomarker-driven patient stratification, and a focus on aging-related mechanisms. This synthesis provides a roadmap for transforming IPF from an incurable terminal illness into a manageable condition, emphasizing quality of life and personalized care.