Abstract Introduction Progressive pulmonary fibrosis (PPF) is characterized by chronic epithelial injury and defective repair, leading to irreversible scarring and respiratory failure. Lung epithelial cells are critical for alveolar regeneration, with their behaviours shaped by cues from the surrounding mesenchymal niche. Loss of Factor inhibiting HIF (FIH) has recently been identified to promote aberrant extracellular matrix deposition, however the consequences upon epithelial-mesenchymal crosstalk are poorly understood. Methods We employed a mesenchymal-specific FIH knockout mouse model (Pdgfrb-Cre ΔHif1an) and a human 3D co-culture system comprising CRISPR-edited FIH-deficient fibroblasts and epithelial cells. Single-cell RNA sequencing was performed on mouse lung tissues to assess epithelial and mesenchymal responses to mesenchymal FIH deletion in vivo. Bulk RNA sequencing was used to profile transcriptional changes in the in vitro 3D co-culture system. Ligand-receptor interaction analysis was conducted to identify disrupted signalling pathways. Findings are being further investigated using primary human lung epithelial cells co-cultured with FIH-deficient fibroblasts. Results Mesenchymal FIH deletion led to impaired epithelial cell identity, as reflected by transcriptional changes both in vivo and in vitro. Cell-cell communication analysis revealed distinct mesenchymal-epithelial signalling disruptions, including aberrant activation of fibrotic and differentiation-related pathways. Conclusions FIH may function as a regulator of mesenchymal-epithelial interactions. This abstract is funded by: AAIR Charity
Zheng et al. (2026) studied this question.