BACKGROUND: The incidence of spontaneously ruptured hepatocellular carcinoma (srHCC) has been shown to significantly elevate mortality rates. However, the precise mechanisms underlying srHCC remain poorly understood. METHODS: Analysis was conducted on the data of 198 hepatocellular carcinoma (HCC) patients to investigate the factors contributing to srHCC. The clinical data of 33 transcriptome HCC patients were served for verification. An in-depth transcriptome analysis was conducted to investigate the distinctions between 26 cases of srHCC and 35 cases of non-ruptured hepatocellular carcinoma (nrHCC). Weighted Gene Co-expression Network Analysis (WGCNA) tool was utilized to develop a gene co-expression network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathways enrichment, and protein-protein interaction (PPI) network were carried out. The corresponding samples for spontaneously ruptured hepatocellular carcinoma tissue (srHCC-T) and ruptured hepatocellular carcinoma paracancerous tissue (srHCC-P) was selected for verification. Transcriptional data were validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR). Immunofluorescence (IF), immunohistochemistry (IHC) and Western blot were used to detect the protein expression. RESULTS: Our results showed that white blood cell (WBC) and monocyte levels were significant independent risk factors for srHCC (P <
0.05). There was a strong association between the srHCC-T and the expression of cell cycle-related genes BUB1B and macrophage function-related gene MACRO. Furthermore, chemokines and the PI3K/AKT signaling pathway play a crucial role in regulating the cell cycle process through a complex network of interactions, ultimately impacting the occurrence of srHCC. CONCLUSIONS: Our study confirms that chemokines and the PI3K/AKT signaling pathway mediate the occurrence of HCC rupture by regulating the cell cycle. We provide a theoretical basis for the clinical treatment of srHCC.