SDF4: a novel prognostic biomarker and therapeutic target in hepatocellular carcinoma revealed by integrated multi‑omics analysis.

Background: SDF4 is a calcium-binding protein with limited research in cancer, particularly liver hepatocellular carcinoma (LIHC). This study aims to clarify its expression and prognostic significance in LIHC, explore its regulatory effects on the tumor microenvironment (TME), and assess its relationship with drug sensitivity for new diagnostic and therapeutic strategies. Methods: This investigation assessed the prognostic value of SDF4, constructed a predictive nomogram, and examined drug sensitivity through molecular docking simulations. Leveraging a single-cell RNA sequencing (scRNA-seq) dataset, we characterized cellular subsets and SDF4 expression patterns within the LIHC microenvironment. Cellular developmental trajectories and intercellular signaling networks were elucidated via pseudotime and CellChat analyses, respectively. Furthermore, we conducted in silico gene knockout experiments alongside comprehensive pathway enrichment assessments. The spatial distribution of SDF4 in liver malignancies was mapped using spatial transcriptomics and subsequently confirmed by immunohistochemical staining. Results: SDF4 exhibited significant overexpression in LIHC tissues and was independently linked to an unfavorable prognosis. Elevated SDF4 levels were associated with more advanced pathological tumor stage (T stage) and clinical stage, establishing it as a reliable prognostic marker, especially in early-stage tumors and older patients. The developed nomogram provided accurate predictions for overall survival (OS) at 1, 3, and 5 years. SDF4 expression showed a significant correlation with sensitivity to multiple anti-cancer agents, and molecular docking studies suggested possible binding interactions. Single-cell sequencing analysis indicated that high SDF4 expression was linked to an enrichment of tumor cells. In silico knockout analysis suggested that SDF4 depletion led to upregulation of genes involved in immunoglobulin-related and complement/coagulation cascades. Pseudotime trajectory analysis demonstrated that elevated SDF4 expression promoted complex evolutionary paths within the TME. Cell-cell communication analysis further confirmed that high SDF4 expression strengthened interaction networks, particularly enhancing signaling from tumor cells to cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and CD8+ T cells. Spatial transcriptomic analysis revealed that SDF4 exhibited significant enrichment within tumor cell regions of LIHC. Immunohistochemical analysis validated the elevated expression of SDF4 in human hepatocellular carcinoma specimens. Conclusions: Our research highlights SDF4's crucial role in hepatocellular carcinoma, suggesting it as a therapeutic target and a biomarker for prognosis, while influencing tumor progression and drug response.