Mechanotransduction Reshapes Epithelial Fate in Lung Ischemia/Reperfusion Injury Through Piezo1-dependent Calcium Signaling

Background. Lung ischemia/reperfusion injury (IRI) remains a major cause of primary graft dysfunction after lung transplantation. Although oxidative stress and inflammation are well-established contributors, the role of biomechanical stress and mechanotransduction in lung IRI has not been fully elucidated. Methods. Public transcriptomic datasets were integrated for differential expression and functional enrichment analyses. Cross-referencing with mechanosensitive ion channel genes identified 5 candidates associated with lung IRI, with Piezo-type mechanosensitive ion channel component 1 (Piezo1) prioritized following independent dataset validation. Rat lung transplantation and in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) models were used to investigate the role of Piezo1 in lung IRI. Piezo1 expression, epithelial injury, calcium accumulation, mitochondrial membrane potential, and apoptosis were evaluated. Genetic knockdown and pharmacological modulation of Piezo1 were performed to determine its functional role. Results. Piezo1 was identified as a mechanosensitive gene associated with lung IRI and was increased following reperfusion. In transplanted lungs, increased Piezo1 expression was accompanied by pulmonary epithelial apoptosis. In human bronchial epithelial cells, OGD/R induced Piezo1 upregulation, intracellular calcium overload, mitochondrial membrane depolarization, and apoptosis. Piezo1 silencing or inhibition alleviated calcium accumulation, preserved mitochondrial membrane potential, reduced apoptotic signaling, and improved cell viability, whereas pharmacological activation of Piezo1 with Yoda1 partially restored the OGD/R-induced injury phenotype in Piezo1-knockdown cells. Conclusions. This study suggests Piezo1 as a potential mechanosensitive regulator of pulmonary epithelial injury during lung IRI, linking biomechanical stress to calcium overload, mitochondrial dysfunction, and apoptosis. Targeting Piezo1-mediated mechanotransduction may represent a potential therapeutic strategy for mitigating graft injury after lung transplantation.