# Macrophage–Derived Ferritin Exacerbates Silica‐Induced Pulmonary Fibrosis via PIK3R2‐Mediated Fibroblast Differentiation

## TL;DR

Macrophage-derived ferritin worsens silica-induced lung fibrosis by promoting fibroblast differentiation through PIK3R2/SMAD signaling, offering new diagnostic and therapeutic possibilities.

## Contribution

Identifies ferritin as a novel mediator and potential therapeutic target in silicosis via macrophage-fibroblast crosstalk.

## Key findings

- Ferritin levels are elevated in silicosis patients and silica-exposed mice, and exogenous ferritin worsens fibrosis.
- Macrophage-secreted ferritin promotes fibroblast differentiation via the PIK3R2/SMAD signaling axis.
- Genetic knockdown of ferritin in macrophages reduces fibrosis and collagen accumulation.

## 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.

This study identifies ferritin as a pivotal mediator of silica‐induced pulmonary fibrosis. Macrophage‐derived ferritin drives fibroblast‐to‐myofibroblast differentiation via the PIK3R2/SMAD pathway, while ferritin knockdown alleviates fibrosis. These findings define ferritin as both a biomarker and pathogenic driver, highlighting ferritin‐PIK3R2 signaling axis as a promising cross‐cellular therapeutic target for silicosis.