Single-cell Transcriptomic Architecture Reveals Dynamic Heterogeneity and Intracellular Crosstalk Features Which Triggers Liver Mallory-Denk Bodies Pathogenesis

Liver cell injury causes balloon hepatocytes and Mallory-Denk Bodies (MDBs) formation impeding liver parenchymal regeneration. MDBs are an intracellular deposition of misfolded protein and typical features of distinct chronic liver disease. Therefore, a comprehensive understanding of cellular heterogeneity and intercellular signaling of MDBs formation is essential to elucidate the mechanisms driving MDBs formation and chronic liver disease progression and to develop therapeutic approaches. Herein, we performed single-nucleus RNA-sequencing (snRNA-seq) to illustrate the comprehensive transcriptomic landscape and intercellular ligand-receptor signaling on the fractionations isolated from healthy and MDB-forming mouse livers induced following DDC. In addition, we applied an MDB-forming cell model induced by cytokines combined clinical hepatocellular carcinoma specimen which had formed MDBs to further verify the potential MDB-forming markers. The results of the analyses were validated using typical MDB-related immunofluorescence staining, bulk transcriptomic datasets, and functional experiments in vitro and in vivo.