Epidemiological data identify colorectal cancer as the second leading cause of cancer-related death globally [1], accounting for nearly one million fatalities annually. Despite advances in screening, surgery, and systemic therapy, the overall survival of patients with advanced CRC remains unsatisfactory [27]. Invasion and metastasis are responsible for ∼90% of CRC deaths [2]; thus, dissecting the molecular machinery that underpins dissemination is an urgent clinical priority.

EMT is a tightly orchestrated programme [3] in which epithelial cells lose apical–basal polarity and cell–cell adhesions, acquire mesenchymal traits, and exhibit heightened motility and invasiveness. Although indispensable during embryogenesis and wound repair, aberrant EMT activation [4] in the tumour microenvironment promotes metastasis. Elucidating the upstream regulators of EMT in CRC is therefore essential for developing targeted interventions.

Piezo1, a Ca²⁺-permeable mechanosensitive ion channel, translates mechanical cues into biochemical signals. Accumulating evidence implicates Piezo1 in tumorigenesis and progression across multiple malignancies [5], [6]. In gallbladder [7] and ovarian [8] cancers, Piezo1 promotes EMT via the Hippo–YAP axis; in hepatocellular carcinoma [9], it recruits Rab5c to potentiate TGF-β [25] signalling. In CRC [5] and gastric cancer [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], Piezo1 upregulates HIF-1α to stimulate angiogenesis and EMT. Moreover, we previously reported that Piezo1 sustains intestinal fibrosis in Crohn’s disease by maintaining HIF-1α levels to promote EMT [11]. These findings collectively position Piezo1 as a key, yet context-dependent-, regulator of EMT.

By interrogating The Cancer Genome Atlas (TCGA) and validating our findings using clinical specimens, we confirmed that Piezo1 is overexpressed in CRC and is associated with poor survival. Therefore, the present study investigated how Piezo1 mechanistically drives CRC invasion and metastasis, with a focus on its interplay with PI3K/Akt signalling and EMT.