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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\u2012epithelial 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-\u03baB and STAT3 pathways via protein phosphorylation. The activated HGF\/MET pathway promotes ubiquitin D (UbD) upregulation and the release of the proinflammatory cytokine TNF\u03b1 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 TGF\u03b21 secretion, thereby accelerating fibrosis in 3D MDB organoid cultures. Notably, UbD deficiency (in UbD\u207b\/\u207b 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.<\/jats:p>","DOI":"10.1038\/s41392-026-02722-4","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T23:01:50Z","timestamp":1781132510000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unraveling the HGF\/MET axis in Mallory-Denk body pathogenesis associated with liver fibrosis through single-cell transcriptomics"],"prefix":"10.1038","volume":"11","author":[{"given":"Xiaoping","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoping","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanhou","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanmei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3585-042X","authenticated-orcid":false,"given":"Xingguang","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinge","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiuying","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangtao","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinru","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongchang","family":"Ouyang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichun","family":"Dang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel W.","family":"French","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7421-8155","authenticated-orcid":false,"given":"Xinghua","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"2722_CR1","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/j.jhep.2017.06.014","volume":"67","author":"V Marin","year":"2017","unstructured":"Marin, V. et al. 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