ArticleSignal transduction and targeted therapy2026
Unraveling the HGF/MET axis in Mallory-Denk body pathogenesis associated with liver fibrosis through single-cell transcriptomics.
Article in Signal transduction and targeted therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Mallory-Denk bodies (MDBs) are protein aggregates commonly observed in chronic liver diseases, including liver fibrosis. However, the intrahepatic crosstalk driving MDB pathogenesis and fibrosis progression remains poorly understood. Using single-nucleus RNA sequencing (snRNA-seq), we identified significant cellular heterogeneity and a distinct hepatocyte subpopulation, termed MDB-associated hepatocytes (MAHs). MAHs were strongly correlated with hepatocellular carcinoma progression. Four hepatic stellate cell (HSC) subpopulations were defined, among which activated HSCs (aHSCs) represent a unique MDB-associated subtype. Moreover, we revealed a tightly connected axis involving MAHs, aHSCs, and Kupffer cells (KCs), which demonstrated that aberrant hepatocyte growth factor (HGF)/mesenchymal‒epithelial transition factor (MET) signaling contributes to MDB pathogenesis. Mechanistically, HGF secreted by aHSCs or KCs interacts with MET on ballooned MAHs and stimulates the HGF/MET downstream PI3K/AKT/NF-κB and STAT3 pathways via protein phosphorylation. The activated HGF/MET pathway promotes ubiquitin D (UbD) upregulation and the release of the proinflammatory cytokine TNFα which further promotes HGF transcription, establishing a positive feedback loop and contributing to MDB formation. Furthermore, aHSCs promote MDB pathogenesis by regulating STAT3 via the HGF/MET axis and increase HSC activation by stimulating TGFβ1 secretion, thereby accelerating fibrosis in 3D MDB organoid cultures. Notably, UbD deficiency (in UbD⁻/⁻ mice) suppressed HGF/MET signaling and MDB formation, leading to reduced liver fibrosis. Consistently, HGF/MET signaling was markedly elevated in human liver biopsies containing MDBs. Together, these findings provide unprecedented single-cell insights into liver cell reprogramming and intrahepatic crosstalk during MDB pathogenesis, and highlight the HGF/MET/UbD axis as a potential therapeutic target for chronic liver disease.
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