Cell type-resolved analysis identifies LOXL2⁺ fibroblasts as key drivers of malignant stromal remodeling in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) typically progresses within a fibrotic, collagen-rich microenvironment where extracellular matrix (ECM) remodeling critically dictates tumor malignancy. However, the cell-type-specific contributions of the lysyl oxidase (LOX) family to this remodeling remain poorly understood. In this study, we conducted an integrative transcriptomic analysis of the LOX gene family (LOX, LOXL1-4) in HCC. Bulk RNA-seq analysis revealed that LOX, LOXL2, and LOXL4 were significantly upregulated in tumors and correlated with advanced pathological stages and poor prognosis. Single-cell RNA-seq (scRNA-seq) analysis delineated distinct expression landscapes: LOX and LOXL4 were enriched in malignant cells, while LOXL2 was predominantly expressed in fibroblasts and endothelial cells. Notably, we identified a discrete LOXL2⁺ fibroblast subset characterized by transcriptomic programs associated with ECM remodeling, contractility, angiogenesis, and hypoxia. A signature derived from LOXL2⁺ fibroblasts was significantly associated with inferior overall survival and enhanced epithelial-mesenchymal transition (EMT) activity in the TCGA-LIHC cohort. Intercellular signaling analysis (CellChat) demonstrated that LOXL2⁺ fibroblasts engage in robust crosstalk with malignant cells via collagen/periostin-integrin signaling axes. Finally, STIP1 was identified through LASSO and random survival forest models as a critical prognostic effector within the LOXL2⁺ fibroblast program. Our findings establish LOXL2⁺ fibroblasts as a pivotal stromal subset driving malignant remodeling and provide potential therapeutic targets for HCC.