Piezo1 signaling facilitates capillarization of LSECs and contributes to liver fibrosis progression

Background Liver fibrosis arises from chronic injury-induced ECM stiffness, activating HSCs and disrupting sinusoidal homeostasis. LSECs undergo capillarization under mechanical stress, exacerbated by hemodynamic changes and ECM stiffness. The mechanosensor Piezo1 mediates this process via Ca²⁺ signaling, linking ECM stiffness to fibrotic progression, highlighting its therapeutic potential. Experimental Approaches Piezo1-knockout C57BL/6 mice were treated with CCl ₄ to induce hepatic injury, followed by histopathological and biochemical analyses. Meticulous and comprehensive studies were performed in vitro using molecular approaches and stable cell lines. Results We demonstrated that increased matrix stiffness upregulates Piezo1 in LSECs, promoting capillarization. Piezo1 activation triggers Ca²⁺ overload, which stimulates MCU-dependent ROS production, leading to HIF-1α stabilization and subsequent pro-fibrotic cytokine release. Genetic inhibition of Piezo1 attenuates LSEC capillarization, reduces HSC activation, and ameliorates liver fibrosis in mice, highlighting Piezo1 as a potential therapeutic target. Conclusion Our findings reveal that mechano-activated channel Piezo1, triggered by elevated shear stress and ECM stiffening, regulates LSEC-dependent capillarization and HSC activation through the Ca²⁺-mROS-HIF-1α pathway and downstream pro-fibrotic mediators. Pharmacological inhibition of Piezo1 in LSECs may hold promise as an anti-fibrotic treatment.