Piezo1-PHLPP2-PI3K/AKT axis represents a novel signalling cascade driving EMT and local invasion in colorectal cancer.

Colorectal cancer (CRC) is a highly prevalent and lethal malignancy worldwide; invasion and metastasis are the principal causes of mortality. Epithelial-mesenchymal transition (EMT) is a pivotal driver of tumour dissemination. Piezo1, a mechanosensitive ion channel that is widely expressed and enables cells to perceive and respond to mechanical cues, is markedly upregulated in CRC tissues and is strongly correlated with poor prognosis. Using in vitro assays, animal models, and clinical specimens, we demonstrated that Piezo1 depletion markedly impairs CRC cell migration and invasion and reverses EMT. Mechanistically, Piezo1 governs EMT by modulating PHLPP2, thereby regulating PI3K/Akt signalling. Orthotopic xenografts established from Piezo1-silenced cells exhibited slower growth, smooth encapsulation, well-defined borders, and diminished stromal content, corroborating the in vitro findings. Collectively, the results of our study elucidate the role of the Piezo1-PHLPP2-PI3K/Akt axis as a critical regulator of CRC dissemination and provide a preclinical rationale for targeting this signalling cascade to improve patient outcomes.