P24 Cellular senescence-triggered dysfunction of hepatocyte aggravates autoimmune liver injury

<h3></h3> Autoimmune hepatitis (AIH) is an inflammatory liver disease characterized by immune cell-mediated autoimmune response against liver autoantigens. However, little is known about the role of hepatocyte senescence in AIH pathogenesis. A novel murine AIH model was established by inhibiting hepatocyte cytokinesis. Cellular senescence was assessed through SA-β-Gal staining and senescent associated secretory phenotype assay. Biochemical and histopathological experiments were performed to detect the hepatic function and liver injury in AIH model. scRNA sequencing was carried out to explore the cellular transition and transcriptomic profile of hepatocyte in AIH. Therapeutically, the efficacy of senolytic treatment (dasatinib plus quercetin) was also investigated in murine AIH model. Inhibition of cytokinesis induced senescent phenotype in hepatocyte, demonstrating as cell cycle arrest, morphological changes as well as senescent associated secretory phenotype. The liver with senescent hepatocytes exhibited AIH features, including increased ALT and AST levels, presence of autoantibodies and severe interface hepatitis and fibrosis on liver histology. scRNA sequencing analysis revealed an unique hepatocyte cluster with senescent characteristic in AIH liver, which strongly communicated with CD8+ tissue-resident memory (TRM) T cells. Mechanistically, the senescent hepatocytes could activate CD8+ TRM T cells and aggravate autoimmune liver injury in a CD44-dependent manner. Unexpectedly, when the AIH mice were treated with senolytic drugs, the liver injury was dramatically alleviated. The increased hepatocyte senescence was also found in AIH patients compared with healthy persons and the senescence proportion was correlated with clinicopathological features. This study established a novel murine AIH model and revealed the critical role of hepatocyte senescence in AIH pathogenesis. The senolytic treatment is highlighted as a promising therapeutic strategy for AIH.