Comprehensive Evaluation and Validation Reveal Mitochondrial Solute Carrier SLC25A3 as a Novel Prognostic Biomarker and Therapeutic Target in Hepatocellular Carcinoma

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Objective: The Solute carrier family 25 member 3 (SLC25A3), a mitochondrial solute carrier protein, has been implicated in tumor progression. Nonetheless, the connection between SLC25A3 and hepatocellular carcinoma (HCC) remains ambiguous. Methods: The expression, mutation, clinical relevance and immune cell infiltration of SLC25A3 in HCC were investigated via integrated bioinformatics analysis using TCGA data. Hub genes were identified by constructing a protein-protein interaction (PPI) network, and the prognostic risk model was established using univariate Cox and LASSO regression analyses. The potential biological functions of SLC25A3 in HCC were elucidated through GO and KEGG analysis using SLC25A3 co-expressed genes. SLC25A3 expression and promoter methylation status in HCC cells was validated by qRT-PCR and bisulfite sequencing PCR, and the biological function of SLC25A3 in HCC was verified through in vitro loss-of-function experiments. Results: SLC25A3 was significantly upregulated in HCC, accompanied by hypomethylation of its promoter region. Elevated SLC25A3 expression was positively correlated with T stage, histologic grade, AFP level, vascular invasion, residual tumor, and unfavorable prognosis, and served as an independent prognostic factor. SLC25A3 expression was correlated with infiltration of multiple immune cell types. The top 10 SLC25A3 associated-hub genes (SNRPF, SNRPB, SNRPE, SNRPD1, SNRPG, EFTUD2, SNRNP200, SF3A3, SNRPA1, LSM2) were recognized. A four-gene prognostic signature derived from SLC25A3-related hub genes (SNRPB, EFTUD2, SF3A3, and SNRPA1) demonstrated favorable predictive performance. Functional enrichment analysis disclosed that SLC25A3 co-expressed genes were predominantly engaged in RNA splicing, ribosome biogenesis, chromosome segregation, cell cycle and DNA replication. Experimental validation further confirmed that SLC25A3 was remarkably raised in HCC cell lines, with its promoter region displaying a hypomethylated status, and silencing of SLC25A3 suppressed proliferation, migration, and invasion while promoting apoptosis in HCC cells. Conclusion: SLC25A3, a member of the mitochondrial solute carrier family, may function as a novel prognostic biomarker and therapeutic target for HCC.

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