Abstract / Summary
Background: YTHDC1 is a nuclear N6-methyladenosine reader involved in RNA processing. Its abundance, cellular distribution, and relationship with the immune microenvironment in hepatocellular carcinoma (HCC) remain incompletely characterized.
Methods: We integrated paired tumor-adjacent transcriptomic and proteomic cohorts, three single-cell RNA-sequencing datasets containing 249,080 quality-controlled cells, four outcome cohorts, three immune checkpoint inhibitor (ICI) cohorts, paired clinical specimens, and cell-based YTHDC1-knockdown assays. Patient-level analyses covered hepatocyte programs, immune states, expression-supported ligand-receptor axes, survival, ICI response, and exploratory single-cell network perturbation.
Results: YTHDC1 protein abundance was higher in 160 paired CPTAC samples (Hedges' g = 1.21, 95% confidence interval [CI] 1.01-1.42), whereas RNA effects varied across cohorts. Single-cell analysis localized YTHDC1 across hepatic and immune compartments and identified patient-level associations with hepatocyte, lymphoid, and myeloid programs. SPP1-CD44 received the strongest cross-cohort expression support among prespecified hepatocyte-to-myeloid axes. A transferred hepatocyte state showed a pooled tumor-adjacent effect of g = 0.42 (95% CI 0.04-0.80), and higher YTHDC1 abundance was associated with poorer overall survival in study-aware univariable models (hazard ratio 1.20, 95% CI 1.06-1.36). In 37 ICI-treated patients, the pooled responder-nonresponder effect for YTHDC1 was small (g = 0.05, 95% CI -0.60 to 0.71). Exploratory virtual knockout showed modest cross-cohort agreement in network perturbation ranks. Paired clinical tissues supported increased YTHDC1 mRNA and protein abundance, and YTHDC1 silencing reduced proliferation-related readouts and THP-1 migration in two HCC cell lines.
Conclusions: YTHDC1 is increased at the protein level in HCC and is situated within identifiable hepatocyte and immune programs. Functional assays support its contribution to HCC cell proliferation and tumor cell-dependent macrophage-like cell migration under the tested conditions.