The inflammatory state of tumor peripheral liver tissue affects hepatocellular carcinoma progression and prognosis.

[UNLABELLED] Inflammation plays a vital role in the initiation and progression of hepatocellular carcinoma (HCC). Whether the inflammatory state of HCC peripheral liver tissue also affects tumor progression remains unclear. The medical data of HCC patients at Nanjing Drum Tower Hospital was retrospectively reviewed. Patients were divided into two groups on different inflammation grades in the peritumoral liver tissue: G 0–1 and G ≥ 2. As a preliminary exploration, RNA-seq was conducted on a limited cohort of six HCC tissues (three per group). Gene Set Enrichment Analysis (GSEA) was conducted to detect differential activation of Hallmarks pathways. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were conducted on differentially expressed genes between these two groups to elucidate enriched pathways and biological processes. Integrated machine learning algorithms and multivariate Cox regression analysis were used for prognostic gene screening and model establishment. 163 patients were included in the G 0–1 group and 207 patients in the G ≥ 2 group. More significant liver fibrosis, as well as severe coagulation and hepatic function impairment, were related to the G ≥ 2 group. Inflammatory genes, hepatic fibrosis-related genes, and Hallmarks pathways INFLAMMATORY_RESPONSE were significantly upregulated in the G ≥ 2 group. Conversely, coagulation factors, complement molecules, fibrinolysis-related molecules, hepatic metabolism-related genes, and Hallmarks pathways COAGULATION and BILE_ACID_METABOLISM were markedly upregulated in the G 0–1 group. KEGG and GO enrichment analyses yielded results consistent with above findings. The established model based on seven inflammatory-related genes performed well in prognostic prediction and risk stratification across multiple datasets. HCC patients with G ≥ 2 had an inflammatory and fibrotic phenotype with a worse prognosis, while patients with G 0–1 retained better coagulation and liver metabolic functions.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s12672-026-04726-6.