Single-cell multiomics reveals endothelial mechanosensitive PIEZO1 coupling IL-33 regulates the development of pulmonary fibrosis

Pulmonary fibrosis (PF) is a lethal lung disease characterized by aberrant lung scarring. Vascular endothelial cells (VECs), which activate fibroblasts through secreting pro-fibrotic molecules, are vital for the PF development. However, the regulatory mechanisms are not fully understood. Here, by employing single-cell multiomics to analyze samples from PF patients and bleomycin (BLM) and SiO2-induced PF mouse models, we discovered that increased mechanical force and mechanosensitive PIEZO1 on VECs are closely associated with PF development, Subsequently, EC-specific deletion of PIEZO1 significantly reduced BLM-induced mouse PF, thereby further validated the critical role of endothelial PIEZO1 in PF. Mechanistically, PIEZO1 activation couples with a pro-fibrotic molecule interleukin-33 (IL-33) to drive the PF development via calpain-2 (CAPN2)-signal transducer and activator of transcription 3 (STAT3) axis. Additionally, PIEZO1 antagonist GsMTx4 effectively alleviated fibrotic outcome, while agonist YODA1 exacerbated the results in mouse model. Our findings reveals the therapeutic potential of mechanosensitive pathways for PF.