Liver cancer is the fourth leading cause of cancer death worldwide, and hepatocellular carcinoma (HCC) accounts for the greatest proportion of these deaths. Baicalein, a flavonoid isolated from the root of Scutellariae radix, is considered a potential candidate to treat HCC. However, the underlying molecular mechanisms remain poorly understood. In the present study, a network pharmacological approach was combined with microarray data (GSE95504) acquired from the Gene Expression Omnibus database to reveal the therapeutic mechanisms of action of baicalein at a systemic level. We identified 38 baicalein targets and 76 differently expressed genes (DEGs) following treatment with baicalein, including 55 upregulated and 21 downregulated genes. The DEGs were significantly enriched in the biological functions of apoptosis, endoplasmic reticulum stress, and PERK-mediated unfolded protein response. Protein-protein interaction (PPI) network construction and topological screening revealed a core module of PPIs including two baicalein targets, TP53 and CDK1, and two downregulated DEGs, HSPA1A and HSPA1B. Expression and survival data for these genes in the module derived from Gene Expression Profiling Interactive Analysis (GEPIA) were subjected to Kaplan-Meier analysis of overall survival and disease-free survival. Overexpression of CDK1, BRCA1, TUBB, HSPA1A, HSPA1B, and HSPA4 was associated with significantly worse overall survival, while overexpression of CDK1, CLU7, BRCA1, and TUBB was associated with significantly worse disease-free survival. These data suggest that baicalein exerts therapeutic effects against HCC via a PPI network involving TP53, CDK1, HSPA1A, and HSPA1B.

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