Rebecca J. Salamon, Shally Saini
Pulmonary fibrosis is often framed as a problem of excess collagen causing stiffening of the lung, but that framing misses the more dynamic reality: fibrosis is built through ongoing conversations between fibroblasts, neighboring cells, and extracellular matrix (ECM) that interpret and reinforce injury signals. Over the last three years, single-cell, spatial, and multi-omics tools, paired with lineage tracing and functional models, have revealed distinct fibroblast states, trajectories, and spatial niches with increasing resolution. Here, we summarize emerging principles from this sharpened point of view. First, lung fibroblasts are not a single “myofibroblast” entity, rather they include a spectrum of states, ranging from resident niche-supporting lipofibroblasts, to transitional and inflammatory intermediate states, to CTHRC1 ⁺ pathological states. These transitions are not strictly linear, potentially reversible, and are context-dependent. Second, fibroblast state transitions are shaped by signals from injury-associated epithelial and immune cell populations within multicellular niches. Third, the ECM is not a passive scar, rather an active signaling hub whose composition, crosslinking, and stiffness engage mechanotransduction pathways that reinforce and, in chronic fibrosis, may lock in pathological fibroblast states. These insights motivate more precise therapeutic strategies – targeting fibroblast state-specific vulnerabilities, disrupting the fibrotic niche, and correcting dysregulated mechanosensing – and raise open questions about fibroblast state reversibility and niche plasticity that will shape next-generation approaches.