Front Immunol. 2026 Aug 19;17:1856643. doi: 10.3389/fimmu.2026.1856643. eCollection 2026.

ABSTRACT

BACKGROUND: Metastasis is the primary cause of treatment failure and adverse prognosis in hepatocellular carcinoma (HCC), and the molecular basis of HCC metastasis remains poorly defined. This work investigated the potential mechanisms underlying HCC metastasis through integrated multi-omics analysis of metabolomics and proteomics.

METHOD: This retrospective study included 105 individuals with HCC, with comparative analysis between metastatic and non-metastatic cases. We further evaluated the effects of metastasis on serum metabolomics and proteomics in HCC patients.

RESULT: Widespread disturbances in amino acid metabolism were identified via untargeted metabolomics in HCC patients with metastasis, closely governing inflammation-related metabolic remodeling and oxidative stress responses. Specifically, we identified 91 and 59 distinct differential metabolites capable of indicating HCC metastasis, with the screening criteria set as log₂ fold change > 1.5, adjusted P value < 0.05, and VIP > 1.5 in positive and negative modes, respectively. The alanine, aspartate and glutamate metabolism pathway correlated with HCC-associated lung metastasis, while the gluconeogenesis pathway was linked to HCC-associated bone metastasis. Compared with HCC (non-metastatic hepatocellular carcinoma), the key molecular alterations in the multi-omics network of HCC_M (HCC with metastasis) are implicated in inflammatory metabolic reprogramming, oxidative stress response, gluconeogenesis, glycolysis, and the tricarboxylic acid (TCA) cycle. Twenty-five proteins, including PKM2, PERCK, ALDH2, CPS1, GLS1, GLUD1, GOT1, and SLC38A2, were identified as potential biomarkers for HCC metastasis.

CONCLUSION: By integrating untargeted metabolomic and proteomic profiling, we identified distinct metabolic and proteomic changes linked to HCC metastasis. This work also characterized the pathological characteristics and core pathways underlying HCC metastasis, while identifying potential therapeutic candidates.

PMID:42688489 | PMC:PMC13534100 | DOI:10.3389/fimmu.2026.1856643