-mediated mRNA instability promotes inflammation-driven hepatocellular carcinoma.

[BACKGROUND] The role of 2'-O-methyltransferases in hepatocellular carcinoma (HCC) progression, particularly concerning inflammation, remains unclear. This study investigated their prognostic significance, identified key prognostic target , and elucidated its inflammatory-related biological functions and molecular mechanisms.

[METHODS] Transcriptomic data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) were integrated to data of subtype HCC patients via consensus clustering based on 2'-O-methyltransferase expression. Single-gene survival analysis linked , , , and to prognosis. A four-gene risk model was built. Multivariate COX regression identified independent risk factors. expression and prognostic value were validated clinically using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Functional roles were assessed [Cell Counting Kit-8 (CCK-8), Transwell, apoptosis/cell cycle assays] and (xenograft models). Mechanisms were explored via RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), and inflammatory cytokine detection.

[RESULTS] Consensus clustering defined three subtypes. Subtype 1 (high 2'-O-methyltransferase expression) showed the worst prognosis. and correlated significantly with survival. The four-gene risk model predicted survival across cohorts [The Cancer Genome Atlas (TCGA)/Gene Expression Omnibus (GEO) datasets (GSE54236/GSE144269)]. was an independent risk factor [multivariate Cox, hazard ratio (HR) =2.268, P=0.01] and significantly elevated in HCC tissues. Functionally, knockdown inhibited proliferation and migration; induced G0/G1 arrest; promoted apoptosis ; and suppressed tumor growth . Mechanistically, drove HCC progression by reducing RNA stability of the key anti-inflammatory gene interleukin 1 receptor antagonist (), leading to downregulated tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and enhanced pro-inflammatory signaling.

[CONCLUSIONS] High 2'-O-methyltransferase abundance predicts poor HCC prognosis. is a novel independent prognostic biomarker and oncogenic factor that promotes HCC progression by dysregulating the inflammatory response pathway, highlighting its translational potential in inflammation-driven HCC.