Microgravity suppresses oral squamous cell carcinoma growth through Piezo1-mediated regulation of calcium ion homeostasis and the autophagy pathway

Background: Oral squamous cell carcinoma (OSCC) is the most common form of oral cancer, with metastasis significantly contributing to its poor prognosis. Emerging research suggests that microgravity may exert anti-tumor effects by inducing cell death, although the precise mechanisms remain unclear. Methods: Rotary Cell Culture System (RCCS) was used to simulate microgravity, allowing observation of its effects on the proliferation and migration abilities of tumor cells. Key genes and pathways influenced by simulated microgravity were identified using RNA sequencing (RNA-seq). In the tongue load-bearing tumor mouse model, we utilized a hindlimb unloading (HU) method to simulate microgravity and investigate its impact on tumor growth, as well as to validate the involvement of identified key genes and pathways. Results: Simulated microgravity induced significant morphological changes in OSCC cells, leading to the formation of multicellular spheroids and altering their biological behavior. RNA sequencing identified PIEZO1 as a key mechanosensitive gene upregulated under microgravity, along with the activation of autophagy-related pathways. In vivo experiments using a tongue load-bearing mouse model demonstrated that simulated microgravity suppressed tumor growth, which was associated with enhanced autophagy and disrupted calcium homeostasis. Piezo1 inhibition partially reversed these effects, confirming its critical role in microgravity-induced OSCC suppression. Conclusion: Simulated microgravity suppresses OSCC growth through Piezo1-mediated calcium dysregulation and enhanced mitophagy. Inhibiting Piezo1 reverses these effects, suggesting its potential as a therapeutic target. This study highlights microgravity-based approaches as promising strategies for OSCC treatment.