Idiopathic Pulmonary Fibrosis (IPF), a major global health issue, is marked by epithelial dysfunction, fibroblast activation, extracellular matrix accumulation, and macrophages playing crucial role in the deranged communication. Macrophage phenotypes, defined by distinct metabolic states, have been shown to impact neighboring cells, including protection from ferroptosis, an iron-dependent cell death due to redox imbalance. Interestingly, elevated Fe2+ levels in IPF were found to correlate with lung fibrosis. In this study we aimed to investigate the role of ferroptosis in IPF pathogenesis.

To this end we utilized spatial and single cell transcriptomic analyses and could show ferroptotic activity in fibrotic but not in healthy tissue. FABP4+ macrophages, previously shown not protect neighboring cells from ferroptosis, were found to be adjacent to pro-ferroptotic AT1 and AT2 cells, suggesting their role in alveolar cell loss in IPF. On the other hand, SPP1 macrophages, providing ferroptosis protection, were found near ciliated and club cells, shown to be upregulated in IPF. Additionally, ferroptotic activity in fibroblasts was linked to disease severity, with pro-ferroptotic cells in less fibrotic areas, opposite to cells located in severely affected regions showing lower ferroptotic activity.  

Collectively, we propose here a new role for ferroptosis in IPF pathogenesis and a central role of macrophages in lung cell survival. Thus, manipulating macrophage metabolic states represents a promising IPF treatment approach.