A PIEZO-Gated Mechanotransduction Timing Window Governs Scar Commitment in Wound Healing.

Cutaneous scarring remains a major clinical challenge, often resulting in impaired function, altered tissue mechanics, and poor aesthetic outcomes. Most current anti-fibrotic therapies target late-stage fibrosis, when extracellular matrix deposition and myofibroblast persistence are already established, limiting regenerative benefit. We propose that scar formation is governed not by gradual accumulation of fibrotic signals but by an early mechanically regulated commitment event, that precedes overt fibrosis. We introduce the concept of a PIEZO-gated mechanotransduction timing window, a finite early interval during which mechanical cues determine whether wound repair remains plastic or becomes irreversibly stabilised. In this framework, tensile load, matrix resistance, and spatial confinement generate force signals sensed by PIEZO mechanosensitive ion channels, triggering calcium-dependent pathways that initiate cytoskeletal remodelling and transcriptional reprogramming. When mechanically induced states are amplified through multicellular feedback linking stromal lineage conversion with immune-mediated matrix reinforcement, repair transitions from reversible intermediates to a self-maintaining fibrotic configuration. Window closure occurs once contractility-stiffness feedback establishes mechanical self-reinforcement, rendering lineage identity persistent even if upstream signals decline. This model predicts that therapeutic efficacy depends primarily on timing: early intervention can redirect repair towards regenerative architecture, whereas delayed intervention mainly reduces fibrotic burden without restoring native tissue organisation. The mechanotransduction timing window therefore represents a measurable and potentially actionable control phase for timing-guided regenerative strategies and predictive mapping of fibrotic risk.