Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the excessive accumulation of activated myofibroblasts that deposit extracellular matrix (ECM) protein, leading to progressive scar formation and mechanical stress. However, the cellular origin and fate of myofibroblasts remain controversial, and the mechanisms by which myofibroblasts sense mechanical cues in the lung are unclear. Here, we report that periostin (Postn) is a reliable and distinctive marker for pulmonary myofibroblasts, while ablation of Postn ⁺ myofibroblasts after injury ameliorated lung fibrosis. PIEZO1 was highly expressed in Postn ⁺ myofibroblast and played a vital role in mechanoactivation of Postn ⁺ myofibroblast and development of lung fibrosis. Conditional deletion of Piezo1 in Postn ⁺ myofibroblasts significantly inhibited lung fibrosis by suppressing myofibroblast activation and proliferation. Loss of Piezo1 led to disruption of actin organization and prevention of Yap/Taz nuclear localization, thus shifting the myofibroblasts from a proliferative state into a stressed and apoptotic state. Furthermore, myofibroblast-specific Yap/Taz deletion fully recapitulated the protective phenotypes of myofibroblast- Piezo1 –KO mice. These findings show that periostin marks pulmonary myofibroblasts, and that PIEZO1-mediated mechanosensation is essential for myofibroblast activation in the lung. Targeting PIEZO1 in the periostin-expressing cells is a novel therapeutic option to interfere with fibrotic diseases such as IPF .

Objective: Pulmonary artery hypertension (PAH) is a life-threatening lung disease without effective therapeutic agents. Necroptosis plays a key role in the pathogenesis of PAH. We therefore investigated to identify and validate the potential necroptosis-related genes in PAH by bioinformatics analysis and experiments. Methods: Firstly, the microarray data of PAH (GSE15197) and necroptosis-related genes were obtained from Gene Expression Omnibus (GEO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Then we used the bioinformatics methods to identify the differentially expressed genes (DEGs) between the normal lungs and the lungs of PAH patients and extract the necroptosis-related DEGs. Enrichment analysis and protein-protein interaction (PPI) analysis were performed to screen the hub genes. Module construction and co-expression analysis of hub genes were also conducted. Key transcription factors (TFs) of hub genes were obtained by using the TRRUST website. Finally, the experimental mouse PAH model was performed to verify the expression of hub genes and key TFs by qRT-PCR. Results: A total of 16 necroptosis-related DEGs (10 upregulated genes and 6 downregulated genes) were identified by comparing the normal lungs and the lungs of PAH patients. ClueGO and KEGG enrichment analysis demonstrated these necroptosis-related DEGs were involved in positive regulation of nitric oxide biosynthetic process, programmed necrotic cell death, positive regulation of chemokine production, necroptosis, and NOD-like receptor signaling pathway. 7 hub genes were obtained by cytoHubba, including BAX, XIAP, TLR4, TNF, HSP90AA1, FAS, and TNFSF10. qRT-PCR analysis confirmed that expression of Bax, Tlr4, Tnf, Hsp90aa1, Fas and Tnfsf10 were significantly upregulated, while the expression level of Xiap was not significant in mouse lungs with experimental PAH compared with normal mouse lungs. Conclusion: Our study identified 7 important hub genes related to necroptosis in PAH, which could be used as potential therapeutic targets and provide new insights into further mechanism study for PAH.