SPP1 regulates alveolar type 2 cell-macrophage cross talk and epithelial cell fate in iron-driven lung fibrosis

Pulmonary fibrosis, a life-threatening respiratory condition affecting millions globally, is characterized by progressive lung scarring that severely compromises respiratory function. With few effective treatment options available, it carries a poor prognosis for those affected. Disrupted iron homeostasis is increasingly implicated in its pathogenesis, yet the precise mechanisms linking iron overload to fibrotic progression remain elusive. This study unveils a novel pathway by which iron accumulation orchestrates fibrotic remodeling via secreted phosphoprotein 1 (SPP1)-mediated reprogramming of alveolar type 2 (AT2) cells. Using an integrated approach combining analysis of public single-cell and single-nucleus RNA sequencing datasets with functional validation across multiple murine models of pulmonary fibrosis (iron-induced, bleomycin-induced, and silica-induced), we demonstrate that iron overload within AT2 cells triggers a coordinated transcriptional cascade affecting iron handling, immune cell recruitment, and cellular differentiation. Mechanistically, SPP1 emerges as a key mediator, functioning both externally as a paracrine signal for macrophage recruitment following iron-induced secretion from AT2 cells and internally as a driver of pathological epithelial transitions, specifically fostering the development of a Krt8⁺ alveolar intermediate phenotype. The clinical relevance of these findings is substantiated by analysis of human idiopathic pulmonary fibrosis specimens using publicly available single-cell and spatial transcriptomic datasets. These analyses reveal conserved pathway activation and a distinctive spatial organization of SPP1-expressing AT2 cells within remodeled tissue microenvironments, notably in close proximity to macrophages. By establishing SPP1 as a critical nexus between iron dysregulation and fibrotic progression, our work identifies the SPP1 signaling axis as a compelling therapeutic target for this devastating condition.NEW & NOTEWORTHY This study reveals a novel mechanism linking iron dysregulation to pulmonary fibrosis through SPP1-mediated reprogramming of alveolar type 2 cells. We demonstrate SPP1's dual role: externally coordinating macrophage recruitment and internally directing pathological epithelial transitions toward a Krt8⁺ intermediate state. These findings, validated across multiple mouse models and human specimens, identify the SPP1 signaling axis as a promising therapeutic target, offering new hope for treating this devastating condition where treatment options have historically been limited.