Identification and Validation of the Prognostic Value of PTTG1-Related Genes in Hepatocellular Carcinoma by Mendelian Randomization and Single-Cell Transcriptome Analysis.

[BACKGROUND] hepatocellular carcinoma (HCC) is a major cancer, and PTTG1 alters asparagine metabolism to promote HCC progression, but its diagnostic and prognostic significance in HCC remains unclear.

[OBJECTIVES] This study aimed to evaluate the prognostic value of PTTG1-related genes in hepatocellular carcinoma by integrating Mendelian randomization, transcriptomic analysis, and single-cell sequencing approaches.

[MATERIALS AND METHODS] This study identified PTTG1-interacting differential genes (PTTG1-IDGs) through differential analysis and protein network construction, then applied Mendelian randomization (MR) to assess their causal relationship with HCC. Univariate Cox regression and machine learning methods screened prognostic genes and constructed prognostic model.

[RESULTS] CDC45 and CENPE were prognostic genes with a causal relationship to HCC. Notably, the odds ratios (ORs) of these prognostic genes were close to 1, indicating that although the two genes had a statistically significant causal association with HCC, the independent effect of each allele on HCC risk was weak. This reflected that PTTG1-related genes played a subtle regulatory role rather than a strong direct causal role in the pathogenesis of HCC. nomogram analysis indicated that risk score and pathological T-stage were independent prognostic factors. Immune infiltration and molecular network analysis highlighted the biological value of CDC45 and CENPE. Single-cell analysis demonstrated the key role of hepatocytes in HCC, while pseudotime analysis revealed the distribution of different cell subtypes. Cell communication analysis showed enhanced interactions between PTTG1-highly expressed cells and fibroblasts, myeloid cells, and endothelial cells; experimental validation confirmed elevated expression of CDC45 and CENPE in the HCC group in addition to PTTG1.

[CONCLUSION] Overall, CDC45 and CENPE, as prognostic genes related to PTTG1, provided new research perspectives and potential therapeutic targets for HCC treatment.