From force to fate: Implications of mechanomemory in lung disease

Mechanical cues are increasingly recognized as master regulators of cell behavior in development, regeneration and disease. In fibrotic tissues and solid tumors, aberrant extracellular matrix (ECM) stiffening activates mechanotransduction pathways that reprogram gene expression, metabolism and chromatin architecture. This stiffened microenvironment does not merely act as a transient signal but may also create a mechanotransductive imprint that reinforces signaling pathways, establishing a positive feedback loop that modulates cell behavior through mechanical memory. The concept of mechanomemory, defined as the cellular ability to retain and adaptively respond to past mechanical stimuli, has emerged as a critical player in cell biology offering new insights into how cells interpret and perpetuate biomechanical cues. This "memory" of mechanical stress modulates key processes such as cellular proliferation, epithelial-mesenchymal transition and invasion, contributing to disease progression and resistance against conventional therapies. This review explores the potential role of mechanomemory in the progression of lung diseases. We examine how sustained mechanical signals are encoded through molecular pathways, cytoskeletal adaptations, and epigenetic modifications, leading to persistent pathological cell states. We discuss how this imprinted memory may drive key features of lung disease, including the perpetuation of fibrosis and the acquisition of therapeutic resistance. We propose that targeting mechanomemory could open novel pathways for disrupting the vicious cycle of mechanical stress and lung disease while identifying novel areas for future research.