Macrophage-Derived Ferritin Exacerbates Silica-Induced Pulmonary Fibrosis via PIK3R2-Mediated Fibroblast Differentiation.

Abstract

Silicosis is a progressive and life-threatening fibrotic lung disease caused by crystalline silica. However, targeted therapies remain unavailable due to its incompletely understood pathogenic mechanisms. Here, we identify ferritin as a pivotal mediator of silica-induced pulmonary fibrosis by integrating clinical exploration with experimental validation. We detected persistently elevated ferritin levels in lung tissues and serum from silicosis patients and silica-exposed mice, and demonstrated that exogenous ferritin administration exacerbates fibrosis in vivo. Multi-omics profiling and co-culture experiments revealed that macrophage-secreted ferritin promotes fibroblast-to-myofibroblast differentiation and pathological extracellular matrix (ECM) deposition via the PIK3R2/SMAD signaling axis. Importantly, genetic knockdown of ferritin in macrophages significantly suppressed myofibroblast differentiation and collagen accumulation both in vivo and in vitro. These findings underscore that ferritin functions not only as a potential clinical biomarker for silicosis surveillance but also as a pathogenic driver through macrophage-fibroblast crosstalk, and provide a theoretical foundation for developing integrated diagnostic and therapeutic strategies against silicosis.