Cellular Adaptation to Mechanical Stress Emerges via Cell Shrinkage Triggered by Nonlinear Calcium Elevation

Abstract Organisms constantly encounter unpredictable environmental perturbations, necessitating adaptation to maintain homeostasis. However, the fundamental principles by which organisms identify specific cues and transition to an adaptive state remain unclear. Here, using a mouse mechanical ventilation model and a cell stretch model, it is found that the cellular adaptation to mechanical stress can be induced by applying low amplitude stretches to cells, and demonstrate that the adaptation emerges once a defined stretch threshold is reached. This adaptive state is marked by transient cell shrinkage and reduced membrane tension. Mechanistically, guided by a mathematical model of intracellular Ca2+ dynamics, it is found that when stretch reaches a critical amplitude, it induces Ca2+‐dependent positive feedback, leading to nonlinear Ca2+ elevation. This activates scramblase Anoctamin‐6, promoting extracellular vesicle‐mediated membrane cholesterol efflux. The reduction in membrane cholesterol subsequently activates volume‐regulated anion channels, leading to cell shrinkage and the establishment of mechanical adaptation. These findings reveal a threshold‐dependent mechanism for mechanical adaptation emergence, and propose a promising strategy to develop targeted interventions in mechanical stress‐related disorders.