Abstract: Objective To investigate the effects of extracellular matrix (ECM) remodeling on the prognostic of in hepatocellular carcinoma (HCC) and explore its potential molecular mechanisms. Methods Tissue specimens and clinical data from 116 HCC patients who underwent hepatectomy in Guangxi Medical University Cancer Hospital from 2018 to 2019 were included. Non⁃negative matrix factorization (NMF) was performed for molecular subtyping. Bulk RNA sequencing (bulk RNA⁃seq) data analyzed to investigate the clinical significance and molecular characteristics of the patients with different molecular subtyping. Imaging mass cytometry (IMC) was employed to analyze the collagen cross⁃linking status and tumor proteomic profiles. Single⁃cell transcriptome sequencing (scRNA⁃seq) data from 10 cases of HCC were obtained from the Gene Expression Omnibus (GEO) database, and the differentiation trajectory and state of tumor cells were analyzed using the Monocle2 algorithm in conjunction with the CytoTRACE method. Results HCC patients were successfully stratified into 2 subtypes: S1 (n=25) and S2 (n=91). Compared with S2,  S1 subtype patients demonstrated poorer prognosis, with higher alpha⁃fetoprotein levels (AFP, P<0.001), advanced Barcelona Clinic Liver Cancer (BCLC) stage (P=0.040), and increased microvascular invasion (MVI) incidence (P=0.010). Transcriptomic analysis revealed significant ECM remodeling and collagen signaling activation in S1 HCC. S1 HCC subtype exhibited significantly higher proportions of Type2 and Type3 collagen crosslinking patterns （P<0.001）, and enhanced mechanotransduction pathway activity. S1 HCC tissues displayed decreased expression of hepatocyte markers but increased stem cell and cholangiocyte markers, indicating a dedifferentiation state. These tumors also showed aggressive phenotypes characterized by E⁃cadherin downregulation and vimentin upregulation (all P<0.001). High expression of key regulators of the YAP and Hippo signaling pathways were significantly associated with poor prognosis of patients. Conclusions The S1 HCC subtype demonstrates poor prognosis, characterized by excessive collagen crosslinking and increased matrix stiffness, which facilitates tumor cell dedifferentiation by activating the YAP signaling pathway.

Key words: Hepatocellular carcinoma, Extracellular matrix, Collagen, Mechanical force, YAP signaling pathway