DLC1 Downregulation Is Linked to Fibroblast-Stellate Matrix Programs and Malignant Phenotypes in Hepatocellular Carcinoma

Background Hepatocellular carcinoma (HCC) commonly arises in fibrotic, matrix-rich liver tissue, but whether reduced expression of deleted in liver cancer 1 (DLC1; STARD12) is linked to fibroblast-stellate matrix programs remains unclear. Methods We integrated TCGA-LIHC bulk transcriptomes, paired HCC tissue staining, western blotting, Huh7 knockdown assays, single-cell RNA sequencing (GSE149614) and spatial transcriptomics (GSE238264), with pan-cancer analyses used as contextual evidence. Results DLC1 was reduced in HCC, and DLC1-low bulk and fibroblast-stellate contexts were enriched for extracellular matrix, adhesion, integrin and focal-adhesion programs. Immunohistochemistry confirmed lower DLC1 protein abundance in HCC tissues, and DLC1 knockdown increased proliferation, migration and invasion in Huh7 cells. Single-cell and spatial analyses linked DLC1-low fibroblast-stellate contexts to C1/C3-like matrix programs, with higher adhesion/ECM and ECM-integrin scores in C1-like regions near C3-high regions. Conclusions These findings support an association model connecting DLC1 downregulation with malignant HCC-related phenotypes and ECM-integrin-rich fibroblast-stellate niches, without establishing a direct stromal-remodeling mechanism.