Bacterial extracellular vesicle ssRNA prevents colorectal cancer progression via Piezo1

Single-stranded RNA (ssRNA) can activate the mechanosensitive ion channel Piezo1 in the gut. However, its source and role in colorectal cancer (CRC) remain unclear. In the present study, we demonstrate that ssRNA within fecal extracellular vesicles (FEVs) derived from bacteria, particularly those susceptible to lysis by ursodeoxycholic acid (UDCA), can suppress CRC progression via Piezo1 activation. Gut-specific Piezo1-knockout mice developed more tumors following CRC induction. Similarly, Piezo1-deficient CRC cell lines exhibited increased proliferation with upregulated Wnt/β-catenin signaling. Mechanistically, Piezo1 activation downregulated the transcription factor Zfp281, decreasing the expression of its target gene Lgr5 and dampening Wnt/β-catenin signaling. Notably, oral UDCA administration enhanced FEV rupture, increasing luminal "naked" ssRNA and mitigating high-fat diet-induced CRC in vivo. These findings identify the bacterial ssRNA-Piezo1 axis as a potential therapeutic target in CRC.