Single-cell transcriptomics reveals epithelial-stromal crosstalk underlying fibrotic remodeling in frontal fibrosing alopecia

Frontal fibrosing alopecia (FFA) is a primary cicatricial alopecia characterized by progressive perifollicular fibrosis and irreversible hair loss. We applied single-cell RNA sequencing to lesional scalp skin from patients with FFA and matched controls to define cellular states, lineage trajectories, and regulatory programs within the pilosebaceous unit. Analysis of 38,984 cells revealed preservation of major epithelial, stromal, and immune populations despite substantial transcriptional remodeling. Epithelial cells exhibited compartment-specific stress-associated reprogramming across follicular and interfollicular domains, progressing along directional trajectories enriched for interferon-STAT/IRF and Th1-related regulatory networks. In contrast, fibroblasts showed limited trajectory remodeling and instead displayed a conserved activation program driven by shared transcriptional regulators. These findings support a model of asymmetric epithelial-stromal dynamics in FFA, suggesting that epithelial stress-associated reprogramming may contribute to stromal activation and fibrotic remodeling and highlighting therapeutic opportunities beyond immune-targeted interventions.