Unique Extracellular Matrix Remodeling in Hepatocellular Carcinoma: TP53 GOF- SP1-ADAM9 Axis as a Prognostic and Therapeutic Target

Background Hepatocellular carcinoma (HCC) is the predominant form of liver cancer, necessitating improved prognostic models and therapeutic strategies. While TP53 mutations are established as markers of poor prognosis in HCC, their specific role in extracellular matrix (ECM) remodeling within the tumor microenvironment remains unclear, despite ECM dynamics being critical for tumor progression and metastasis. This study aims to elucidate the relationship between TP53 mutations and ECM remodeling to identify novel prognostic and therapeutic targets. Methods Comprehensive bioinformatics analyses were performed using The Cancer Genome Atlas (TCGA) dataset. Single-sample gene set enrichment analysis (ssGSEA) was used to assess ECM content, while LASSO regression and Cox proportional hazards modeling constructed an ECM-related prognostic signature. Functional validation included RT-qPCR, Western blotting, and in vitro gain/loss-of-function experiments to explore the TP53-SP1-ADAM9 axis. Results ECM content was reduced in HCC tissues compared to normal livers, with 559 ECM-related genes differentially expressed. An 18-gene ECM prognostic signature was established, showing significant association with overall survival. TP53 mutations, particularly gain-of-function (GOF) variants, were linked to upregulated ADAM9 expression. Mechanistically, TP53 regulated ADAM9 via transcriptional factor SP1, with GOF mutations enhancing SP1 binding to the ADAM9 promoter. Conclusions This study identifies a TP53-SP1-ADAM9 axis driving ECM remodeling in HCC. The ECM prognostic signature improves survival prediction, while targeting ADAM9 or SP1 represents a promising therapeutic strategy for TP53-mutant HCC. These findings highlight ECM remodeling as a critical node for prognostic and therapeutic intervention.