Molecular Subtypes of Hepatocellular Carcinoma Defined by Anesthesia‐Related Drug Target Genes During the Perioperative Period and Their Prognosis, Immunological Characteristics, and Drug Response

ABSTRACT Background The use of perioperative anesthetic drugs may influence the prognosis of cancer patients, but the expression characteristics and clinical significance of their associated target genes in hepatocellular carcinoma (HCC) remain unclear. This study aims to establish a molecular subtyping system based on perioperative anesthesia‐related drug target genes (PARDTGs) and systematically evaluate their potential value in HCC prognosis, immune microenvironment, and drug response. Methods To assess HCC prognosis, we established a PAR‐DTG Score derived from PARDTGs. Initial screening in the Cancer Genome Atlas Liver Hepatocellular Carcinoma and GSE14520 cohorts employed differential expression analysis, followed by univariate Cox and Least Absolute Shrinkage and Selection Operator regression to identify prognostic genes. Comprehensive characterization of high‐ and low‐risk groups was subsequently performed, integrating immune infiltration analyses, functional enrichment, tumor mutational burden evaluation, and drug sensitivity predictions to elucidate their distinct molecular and clinical features. Results A prognostic model based on a PARDTG‐derived prognostic signature consisting of five genes (CD24, MCM5, PPARGC1A, SLC22A7, and VNN2) was constructed and demonstrated robust predictive performance across two independent cohorts. Patients in the high‐risk group exhibited significantly reduced overall survival and enrichment in cell cycle‐related pathways (e.g., E2F targets and G2M checkpoint), whereas the low‐risk group showed significant enrichment in metabolic pathways (e.g., fatty acid metabolism and bile acid metabolism). Immune microenvironment analysis revealed elevated expression of B cells, CD8 + T cells, and immune checkpoint molecules in the high‐risk group, which also demonstrated higher response rates to PD‐L1 blockade immunotherapy. Drug sensitivity prediction indicated greater susceptibility to chemotherapy agents such as cisplatin and sorafenib in the high‐risk group. Conclusion The prognostic model constructed based on PAR‐DTG Score effectively distinguishes survival risks among HCC patients and reveals its connections with the immune microenvironment, molecular mechanisms, and drug responses, providing preliminary insights for developing personalized treatment strategies.