Progress on the mechanism of Piezo1 in mechanical ventilation-induced lung injury.

Ventilator-induced lung injury (VILI) causes 40-45% mortality in acute respiratory distress syndrome (ARDS) despite lung-protective ventilation. Current therapies remain empirical, lacking mechanistic understanding of how cells transduce mechanical forces into pathological responses. The mechanosensitive ion channel Piezo1 has emerged as a critical mechanotransducer, yet exhibits a fundamental paradox: endothelial Piezo1 deletion worsens edema while excessive activation disrupts barriers and triggers inflammatory cell death. Conventional "protective versus injurious" frameworks cannot explain these opposing outcomes. We propose the "Context-Dependent Rheostat" model, wherein Piezo1 outcomes depend on mechanical dose, cellular context, and inflammatory milieu. This review synthesizes evidence demonstrating that Piezo1 responses exhibit quantitative inflection points rather than fixed directional effects, with temporal dynamics, cell-type-specific thresholds, and inflammatory priming determining functional transitions. Specifically, endothelial cells preserve barrier integrity within a wider strain tolerance window, whereas epithelial cells exhibit substantially narrower damage thresholds; acute stretch activates protective chromatin remodeling, while sustained ventilation drives ataxia telangiectasia and Rad3-related/checkpoint kinase 1 (ATR/Chk1)-mediated genomic collapse and cellular senescence. Beyond cell-autonomous responses, macrophages emerge as candidate signal-hub cells integrating mechanosensory inputs from endothelial, epithelial, and neutrophil compartments, representing a high-value therapeutic node. This framework fundamentally reframes VILI therapeutics from global Piezo1 modulation toward precision interventions: temporal stage-specific targeting, context-specific threshold resetting, and biomarker-guided stratification. Candidate strategies span nuclear factor erythroid 2-related factor 2 (NRF2) activators for early-phase cytoprotection, Toll-like receptor 4 (TLR4) antagonism, and ATR/Chk1 inhibitors or senolytic combinations for late-phase intervention, guided by circulating DNA-damage marker γH2AX and senescence-associated secretory phenotype markers. We provide a translational roadmap enabling VILI therapy to transition from empirical ventilation adjustment toward mechanistically-guided precision medicine with actionable intervention points.