Extracellular matrix-defined transcriptomic subtypes reveal a CXCL8-enriched fibrotic-inflammatory microenvironment and preliminary radiological associations in hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) is highly heterogeneous, yet extracellular matrix (ECM)-centered subtyping and its potential clinical and biological implications remain insufficiently defined. Methods TCGA-LIHC (n = 371) and GSE14520 (n = 225) served as discovery and independent replication cohorts, respectively. ECM-related transcriptional states were identified by cohort-specific consensus clustering. Single-cell RNA sequencing data from 10 HCC patients were used to characterize the cellular context of CXCL8. Histological assessment, IL-8 immunohistochemistry, and tissue CXCL8 RT-qPCR were performed in 76 HCC specimens from an independent FUSCC cohort. Radiological features were retrospectively reviewed in a limited subset (n = 11). Selected cellular stress- and DNA damage response-related programs were assessed by enrichment analysis. Results ECM-remodeled tumors exhibited distinct stromal-immune features, including fibrotic ECM activation, cancer-associated fibroblast programs, chemokine activity, TGF-β signaling, hypoxia, and macrophage-enriched inflammation. Cross-cohort analysis identified CXCL8 as a candidate gene associated with ECM-remodeled states, poor prognosis, and fibrotic-inflammatory microenvironmental remodeling. Single-cell RNA-seq analysis localized CXCL8 mainly to myeloid cells and an activated ECM-remodeling fibroblast subset. In the FUSCC cohort, higher collagen deposition was accompanied by higher IL-8 H-scores and CXCL8 mRNA expression, both positively correlated with collagen-positive area. Exploratory radiological review suggested associations between the ECM-high/CXCL8-high state and selected adverse imaging features. Exploratory differences in selected cellular stress- and DNA damage response-related programs were observed, without treatment-response endpoints. Conclusion These findings support a CXCL8-enriched fibrotic-inflammatory phenotype in HCC with tissue-level associations between collagen deposition and IL-8/CXCL8 expression, and provide an exploratory, hypothesis-generating link between molecular stratification and radiological features.