Ventral cytoskeletal remodeling as a mechanism for oscillatory load-induced Piezo1 overactivation and cancer cell vulnerability

Abstract The limited selectivity of conventional cancer therapies has stimulated interest in alternative approaches that exploit the distinct mechanical properties of cancer cells. Oscillatory mechanical stimuli, including low-intensity ultrasound and cyclic cellular deformation, represent promising non-chemical strategies capable of inducing selective cancer cell death through activation of the mechanosensitive ion channel Piezo1. However, the mechanisms linking external mechanical loading to Piezo1 overactivation remain insufficiently understood. This review presents a unified mechanobiological framework describing how frequency-dependent remodeling of the ventral cytoskeleton regulates Piezo1 activity in mesenchymal-like cancer cells. The heterogeneous and anisotropic organization of the cancer cell cytoskeleton enables specific mechanical responses, including stress localization, domain twisting under oscillatory extension, and domain tilting under ultrasound stimulation. These remodeling processes alter membrane–cytoskeleton coupling, focal adhesion-associated curvature formation, and Piezo1 conformational dynamics. In particular, torsional loading and curvature-dependent modulation of Piezo1 clusters provide potential mechanisms for sustained channel activation and Ca2⁺-mediated apoptosis. The proposed framework demonstrates that the response to oscillatory mechanical stimulation depends on the interplay between loading parameters and the dynamically remodeled mechanical state of the basal membrane–cytoskeleton system. These insights provide a physical basis for developing mechanically selective anticancer strategies by optimizing oscillatory stimuli to exploit cancer cell-specific vulnerabilities while preserving healthy tissues.