Hepatocellular carcinoma (HCC) is a malignant tumor with high recurrence and metastasis rates and poor prognosis. Basement membrane is a ubiquitous extracellular matrix and is a key physical factor in cancer metastasis. Therefore, basement membrane-related genes may be new targets for the diagnosis and treatment of HCC. We systematically analyzed the expression pattern and prognostic value of basement membrane-related genes in HCC using the TCGA-HCC dataset, and constructed a new BMRGI based on WGCNA and machine learning. We used the HCC single-cell RNA-sequencing data in GSE146115 to describe the single-cell map of HCC, analyzed the interaction between different cell types, and explored the expression of model genes in different cell types. BMRGI can accurately predict the prognosis of HCC patients and was validated in the ICGC cohort. In addition, we also explored the underlying molecular mechanisms and tumor immune infiltration in different BMRGI subgroups, and confirmed the differences in response to immunotherapy in different BMRGI subgroups based on the TIDE algorithm. Then, we assessed the sensitivity of HCC patients to common drugs. In conclusion, our study provides a theoretical basis for the selection of immunotherapy and sensitive drugs in HCC patients. Finally, we also considered CTSA as the most critical basement membrane-related gene affecting HCC progression. In vitro experiments showed that the proliferation, migration and invasion abilities of HCC cells were significantly impaired when CTSA was knocked down.Copyright © 2023 Sun, Wang, Wang, Xu, Lin, Sun and Yuan.