Differential analysis of GADD45A expression in hepatocellular carcinoma: investigating its role and clinical implications through bioinformatics approaches

GADD45A is a stress-responsive nuclear protein, yet its precise role and immune implications in liver hepatocellular carcinoma (LIHC) remain poorly characterized. This study investigated the prognostic value, immune landscape, and cell-intrinsic functions of GADD45A in LIHC. Transcriptomic and clinical data from TCGA and GEO repositories were evaluated using Wilcoxon tests, Kaplan–Meier curves, and Cox models. Pathways and immune infiltration were mapped via STRING, GSEA, and TIMER2.0, followed by in vitro validation (including cytotoxicity, qRT-PCR, Western blot, CCK-8, colony formation, wound healing, and Transwell assays) in modified HepG2 cells , complemented by Western blot and migration/invasion assays in Huh-7 cells. GADD45A was significantly downregulated in LIHC, and its deficiency strongly correlated with advanced pathological stages and poor survival, establishing it as an independent prognostic biomarker. Low GADD45A expression was positively associated with an exhausted immune microenvironment characterized by elevated inhibitory checkpoints (PDCD1, CTLA4, LAG3). In vitro experiments demonstrated that GADD45A overexpression markedly suppressed HCC cell proliferation, colony formation, and metastasis, while concurrently enhancing chemosensitivity to cisplatin. GADD45A functions as a significant cell-intrinsic tumor suppressor and a clinically relevant indicator of the tumor immune landscape in LIHC, representing a promising prognostic biomarker and therapeutic target.