Abstract
<title>Abstract</title> <p> Glioblastoma (GBM) is an aggressive, highly invasive adult brain tumor with a median survival of less than 15 months. As these tumors advance, they exhibit altered tissue mechanobiology, including the elevated expression of mechanosensitive ion channels, such as Piezo1. Focused ultrasound (FUS), used to open the blood-brain barrier for targeted drug delivery into GBM, exerts mechanical forces that could influence these aberrantly expressed channels. However, the specific role of Piezo1 in mediating GBM cellular response to FUS-induced mechanical stress remains unclear. We identified a 6.81-fold upregulation of Piezo1 in U-87 GBM cells compared to healthy brain tissue. Here we show that Piezo1 aids in GBM cellular resistance to FUS, and that targeted Piezo1 knockdown sensitizes cells to acoustic stress. Following sonication, Piezo1 deficiency increased susceptibility to early physical detachment. By 24 hours, control cells demonstrated reduced cell death (-70.2%) and increased proliferation (+ 45.5%), whereas Piezo1-deficient cells maintained significantly elevated dead cell number (+ 28.9%) and exhibited attenuated long-term growth (+ 14.9%). These <italic>in vitro</italic> results suggest that Piezo1 aids in GBM cell resistance to FUS by limiting physical detachment and promoting cell survival, which are required to resolve acute cytotoxicity and facilitate long-term GBM cell proliferation. Therefore, targeted inhibition of Piezo1 may enhance the cytotoxic efficacy of FUS in clinical therapeutic applications. </p>