Abstract:Background and Aims Gamma-aminobutyric acid type A receptor delta subunit (GABRD) has been implicated in the progression of several malignancies, whereas its biological role and therapeutic relevance in hepatocellular carcinoma (HCC) remain largely unknown. This study aimed to investigate the expression pattern, oncogenic function, and potential molecular mechanisms of GABRD in HCC and to identify candidate small-molecule inhibitors targeting GABRD.Methods Public datasets from HCCDB and TCGA, together with clinical specimens, were used to evaluate GABRD expression and prognostic significance. Gain- and loss-of-function models were established using lentiviral overexpression and CRISPR/Cas9-mediated knockout approaches. Cell proliferation, migration, and invasion were assessed by CCK-8, EdU incorporation, colony formation, wound-healing, and Transwell assays. The in vivo effects were evaluated using subcutaneous xenograft, spontaneous HCC, and pulmonary metastasis models. RNA sequencing combined with GO, KEGG, and GSEA analyses was performed to explore downstream mechanisms. Structure-based virtual screening, molecular docking, and molecular dynamics simulations were applied to identify potential GABRD-targeting compounds, followed by in vitro and in vivo validation.Results GABRD was significantly upregulated in HCC tissues and cell lines, and its elevated expression was associated with unfavorable overall survival, disease-specific survival, and progression-free survival. GABRD knockout markedly inhibited HCC cell proliferation, migration, and invasion, whereas GABRD overexpression exerted opposite effects. In vivo studies further demonstrated that GABRD deficiency suppressed tumor growth and pulmonary metastasis. Transcriptomic analyses suggested that GABRD might promote HCC progression through cytokine-cytokine receptor interaction, JAK-STAT signaling, and epithelial-mesenchymal transition-related pathways. Structure-based virtual screening identified memantine as a potential GABRD-binding compound with high binding affinity. Memantine reduced GABRD expression and significantly reversed the pro-tumorigenic effects mediated by GABRD both in vitro and in vivo.Conclusion GABRD acts as an oncogenic regulator in HCC and may serve as a prognostic biomarker and therapeutic target. Memantine suppresses HCC growth and metastasis by targeting GABRD, providing experimental evidence for drug repurposing and novel targeted therapeutic strategies in HCC.