Development and validation of HSP90AA1 as a risk gene in a HIF-1α pathway-related prognostic signature for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a prevalent malignancy with globally increasing incidence and mortality rates. The identification of a robust prognostic signature remains an unmet clinical need in HCC treatment. In this study, transcriptome and clinical data of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) database, and the top 100 HIF-1α pathway-related genes (HPRGs) were selected from GeneCards. Using univariate Cox regression, LASSO-regularized Cox regression, and multivariate Cox regression, a four-gene prognostic signature (HSP90AA1, ANGPT2, NPM1 and LDHA) was established. Its robust predictive performance was validated using receiver operating characteristic (ROC) curve analysis, the concordance index (C-index), and decision curve analysis (DCA). Subsequently, HCC patients were stratified into high- and low-risk groups according to the median risk score, and survival analysis confirmed markedly inferior prognosis for patients in the high-risk group. Furthermore, the expression level of the signature genes correlated positively with risk score and were overexpressed in high-risk HCC tissues in the GSE121248 and GSE14520 datasets. Besides, the drug sensitivity analysis demonstrated that the high-risk group exhibited greater sensitivity to 5-fluorouracil, gemcitabine, paclitaxel, sorafenib, and sunitinib. Mendelian randomization (MR) and Bayesian colocalization analyses validated HSP90AA1 and LDHA as potential druggable targets. Furthermore, functional validation experiments demonstrated that knockdown of HSP90AA1 could impede the proliferation, migration, and invasion of HCC cells. Overall, this research presents a novel prognostic signature for HCC and highlights the potential of HSP90AA1 as a biomarker and therapeutic target.