Piezo1-ATF3-PPP1r15a Axis Transduces Mechanical Stress into Apoptosis in Glioma Under Low-Intensity Focused Ultrasound

Background: Glioblastoma (GBM) is characterized by high morbidity and mortality due to its localization and often locally invasive growth. Current treatment options for GBM are limited, with conventional therapies achieving a median survival of only 15 months. Mechanotherapy has been proposed as a new therapeutic strategy in oncology. Low-intensity focused ultrasound (LIFU), a form of mechanotherapy, has demonstrated inhibitory effects on GBM. However, its underlying mechanisms remain poorly understood. The present study aimed to evaluate the therapeutic effects of LIFU on GBM and investigate its mechanisms of action. Methods: Cell viability and proliferation were evaluated using cell counting kit-8, EdU and colony formation assays, while the effects of LIFU on GBM cell apoptosis were evaluated by flow cytometry. Transcriptome sequencing, immunofluorescence, reverse transcription-quantitative polymerase chain reaction, Western blot, bioinformatics analysis, dual-luciferase reporter assay and chromatin immunoprecipitation were used to investigate the molecular mechanisms underlying the effects of LIFU on GBM. The therapeutic efficacy of LIFU was further validated in a subcutaneous xenograft tumor model, in which tumor size, survival rate and immunohistochemical changes were monitored. Results: The results of the present study demonstrated that LIFU exerts anti-GBM effects by activating Piezo1 and modulating the downstream ATF3/PPP1r15a pathway to regulate apoptosis. LIFU therapy holds promise as a new treatment strategy for GBM, with the potential to improve patient prognosis. Conclusions: LIFU suppresses GBM progression through the Piezo1/ATF3/PPP1r15a axis by activating endoplasmic reticulum stress.