Cancer Rep (Hoboken). 2026 Sep;9(9):e70685. doi: 10.1002/cnr2.70685.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and remains a major cause of cancer-related mortality worldwide. Its poor clinical outcomes are largely attributed to late-stage diagnosis and the limited accuracy of currently available diagnostic and prognostic biomarkers. Therefore, identifying novel molecular markers with improved sensitivity, specificity, and therapeutic relevance is essential for enhancing early detection and guiding personalized treatment strategies.

AIMS: To identify and prioritize novel candidate HCC biomarkers with diagnostic and prognostic value and potential therapeutic vulnerability using integrated multi-omics, survival, functional dependency, and tumor microenvironment analyses.

METHODS AND RESULTS: We examined the mRNA and protein expression levels of 8 DEGs in HCC tissues in the TCGA and CPTAC datasets using UALCAN, which showed that MSTO1 and LIG1 were overexpressed consistently in HCC relative to normal liver tissues. Moreover, elevated expression levels of these genes were significantly associated with higher tumor grade and advanced stage. Kaplan-Meier plotter survival data confirmed that increased expression of MSTO1 and LIG1 was associated with poorer overall survival. The DepMap CRISPR knockout data confirmed a functional dependency of both genes in HCC cell lines. CBioPortal analyses provided characterization of genomic alterations and enabled enrichment analysis of co-expressed genes, and the TCGA-UALCAN pan-cancer analyses supported the assessment of tissue specificity across tumor types. TIMER3 analyses linked candidate gene expression with immune cell infiltration patterns. Diagnostic performance by ROC analysis showed excellent discrimination for MSTO1 (AUC = 0.987) and good discrimination for LIG1 (AUC = 0.897). Multivariate Cox regression with Benjamini-Hochberg FDR correction across the eight genes supported MSTO1 as a candidate independent prognostic factor after adjustment for tumor stage, grade, etiology, age, and sex (HR = 1.29, p = 0.035), whilst LIG1 showed no independent prognostic value. Promoter methylation of MSTO1 and ADH4, assessed via UALCAN, showed that both genes were significantly differentially methylated in the promoter region of primary HCC tissues compared with normal liver tissues. Our study also confirmed the biological and clinical relevance of established HCC biomarkers: TERT, IRAK1, and ADH4.

CONCLUSION: MSTO1 and LIG1 emerged as candidate diagnostic biomarkers in HCC. Additionally, MSTO1 showed a candidate prognostic association with overall survival that remained significant after adjusting for tumor stage, grade, and etiology, as well as patients' age, but not after further adjustment for AFP status. Functional data also highlighted MSTO1 as a candidate therapeutic dependency. On the other hand, LIG1 showed no independent prognostic association in either multivariate model. Their differential expression and functional essentiality in HCC cell lines highlighted their value for further experimental and independent-cohort validation before potential integration into biomarker development pipelines aimed at improving early detection and targeted therapy in HCC.

PMID:42732946 | DOI:10.1002/cnr2.70685

Int Immunopharmacol. 2026 Sep 13;189:117355. doi: 10.1016/j.intimp.2026.117355. Online ahead of print.

ABSTRACT

Immune evasion in hepatocellular carcinoma (HCC) represents a major biological barrier limiting the efficacy of immunotherapy, yet its molecular basis remains incompletely understood. Increasing evidence indicates that tumor metabolic reprogramming and ferroptosis-related signaling play critical roles in shaping an immunosuppressive tumor microenvironment (TME); however, the specific regulatory factors involved remain unclear. This study aims to systematically elucidate the functional role of S100 calcium-binding protein A10 (S100A10) in immune evasion in HCC, with a particular focus on the molecular mechanisms by which S100A10 regulates CD8⁺ T-cell exhaustion through arachidonic acid (AA) metabolism and ferroptosis, as well as its potential therapeutic implications. To this end, data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort are integrated to analyze the expression patterns of S100A10, its prognostic value, and its association with the immune microenvironment. S100A10 overexpression and knockout models are established in HCCLM3 and MHCC97L cell lines, and S100A10-mediated metabolic pathway reprogramming is characterized using transcriptomic profiling, untargeted metabolomics, and ferroptosis-related functional assays. In parallel, single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics are employed to delineate the cell-type specificity and spatial distribution of S100A10. Furthermore, human CD8⁺ T-cell co-culture systems and orthotopic mouse HCC models are used to evaluate the impact of S100A10 on immune function and responsiveness to anti-programmed cell death protein 1 (anti-PD-1) therapy. The results demonstrate that S100A10 is significantly upregulated in HCC and is closely associated with poor prognosis and an immunosuppressive state. Mechanistically, S100A10 activates cytosolic phospholipase A₂-arachidonate 5-lipoxygenase (cPLA₂-5-LOX)-mediated AA oxidative metabolism, leading to the accumulation of lipid peroxidation products and ferroptosis-associated signals, thereby driving CD8⁺ T-cell exhaustion and promoting immune evasion. Significantly, inhibition of S100A10 reshapes the tumor immune microenvironment (TIME) and enhances the therapeutic efficacy of anti-PD-1 treatment. Collectively, these findings identify S100A10 as a critical regulator of metabolic-immune coupling in HCC and provide a theoretical basis for combinatorial strategies targeting metabolism and immunotherapy.

PMID:42732672 | DOI:10.1016/j.intimp.2026.117355