Piezo1 deficiency alleviates acute liver failure by inhibiting CpG-ODN induced inflammatory responses

Macrophages play a critical role in the progression of acute liver failure (ALF), a life-threatening clinical syndrome characterized by the rapid onset of liver injury. Recent research suggests that mechanosensation signaling may be pivotal in modulating acute inflammation. However, its involvement in ALF pathogenesis remains poorly understood. In this study, we found that Piezo1 was highly expressed in liver macrophages during liver injury in both humans and mice. Mice with macrophage-specific Piezo1 depletion were resistant to CpG-ODN/D-GalN-induced ALF, whereas mice pretreated with Yoda1 showed increased susceptibility. Furthermore, Piezo1-deficient macrophages exhibited reduced secretion of inflammatory cytokines upon CpG-ODN stimulation in vitro, while Yoda1 treatment enhanced cytokine secretion. Mechanistically, Piezo1 activation promotes the phosphorylation of CaMKII, which further enhances CpG-ODN-induced NF-κB activation. Additionally, Piezo1 activation promotes the endosomal translocation of TLR9 through the cytoskeleton remodeling. These findings suggest that Piezo1-mediated mechanosensation contributes to the development of CpG-ODN/D-GalN-induced ALF and may serve as a potential therapeutic target.