The Piezo1-Ca2+-PI3k/Akt signaling axis as a context-dependent mechanotransduction node during skin wound healing

Mechanical forces are fundamental drivers of cutaneous tissue repair; however, the molecular mechanisms translating physical cues into fibroblast responses remain incompletely understood. This review examines the Piezo1-PI3K/Akt signaling axis as a putative convergent context-dependent mechanotransduction node, through which multiple mechanical inputs may be transduced into intracellular biochemical cascades. Direct evidence in dermal fibroblasts is strongest for the integrin-FAK arm; we synthesize findings across cell types to propose a multi-pathway framework encompassing four molecular bridges: CaM/CaMK-mediated activation, a synergistic integrin-FAK loop, calpain-mediated regulation, and a Panx1-ATP-P2Y2 paracrine pathway. Beyond signal relay, this axis may function as a spatiotemporal encoder coordinating fibroblast proliferation, migration, metabolic reprogramming, and myofibroblast differentiation. By contrasting physiological healing with dysregulated mechanotransduction in chronic wounds and hypertrophic scars, we highlight the therapeutic relevance of this axis and propose that its modulation may offer a strategy to restore mechanical homeostasis and improve clinical outcomes.