The FAK-STAT3-XIAP signaling axis couples matrix stiffening to ciliary loss to activate hepatic stellate cells

Activation of hepatic stellate cells (HSCs) is a central event of liver fibrosis, yet the underlying mechanisms remain incompletely understood. Herein, we demonstrate that increased stiffness of extracellular matrix (ECM) is coupled to the loss of primary cilia, which leads to HSC activation in both mouse models and human patients with liver fibrosis. Mechanistically, matrix stiffening triggers the focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) signaling to enhance the expression of X-linked inhibitor of apoptosis protein (XIAP). Upregulation of XIAP promotes the ubiquitination of intraflagellar transport protein 88 (IFT88), leading to its proteasomal degradation and subsequent ciliary loss. The disruption of cilia, in turn, elevates the secretion of ECM components to exacerbate matrix stiffening and HSC activation. Collectively, these findings reveal a positive feedback loop between matrix stiffening and ciliary loss, mediated by the FAK-STAT3-XIAP signaling axis, which promotes HSC activation and liver fibrosis.