Multi-omics analysis decipher effect of ECM degradation and depositionon hepatocellular carcinoma

The extracellular matrix (ECM), an important component of the tumor microenvironment, plays a pivotal role in hepatocellular carcinoma (HCC) progression and metastasis. However, the impact of ECM remodeling on HCC pathology via TGF-β signaling remains unclear. In this study, we systematically mapped ECM deposition and degradation in HCC by jointly analyzing scRNA-seq data, scATAC-seq data and ST data, and identified key ECM-regulating cell types Endothelial_Cells, Fibroblasts and Macrophages. Endothelial_Cells and Fibroblasts were primarily responsible for ECM deposition and Macrophages were mainly involved in ECM degradation in HCC. Correlation analysis demonstrated that Macrophages, Endothelial_Cells and Fibroblasts activated the TGF-β signaling pathway through ECM deposition, which negatively regulated the function of the mitochondrial respiratory chain, and especially promoted the mitochondrial fission in Endothelial_Cells, thereby driving the pathological progression of cirrhosis and HCC. Additionally, the cellular microenvironment mediated ECM functions of key cells through FN1 and VTN signaling, further influencing HCC development. The upstream regulatory network analysis recognized ENO1, YBX1, and CEBPD as key transcription factors regulating ECM-related genes and drug target prediction analysis further screened ECM-targeted drugs with therapeutic potential in HCC. In summary, this study highlights Macrophages, Endothelial_Cells, and Fibroblasts as pivotal ECM regulators in HCC and elucidates how ECM deposition in key cells impacts mitochondrial homeostasis through TGF-β signaling, thereby providing new insights into the development of HCC from the perspective of the ECM and offering important guidance for optimizing existing ECM-targeted therapeutic strategies.