<b>RNF115 upregulation by YBX1-dependent m5C modification promotes hepatocellular carcinoma progression</b>

<b>Abstract</b>Our transcriptome-wide profiling revealed significant heterogeneity in m5C modification patterns across hepatocellular carcinoma (HCC), with differentially methylated genes broadly distributed throughout the genome except chromosome Y. The m5C reader protein YBX1 was significantly upregulated in HCC tissues and correlated with poor prognosis. Through integration of m5C MeRIP-seq and YBX1 RIP-seq data, we identified RNF115 as a direct YBX1 target regulated in an m5C-dependent manner. Mechanistically, YBX1 binds to m5C-modified motifs within RNF115 mRNA 3'UTR, enhancing its stability and translation. RNF115 overexpression was associated with advanced tumor stage, increased metastasis, and poor clinical outcomes. Further investigations demonstrated that the YBX1/m5C-RNF115 axis promotes HCC progression primarily via PI3K/AKT pathway activation. These findings elucidate a novel epitranscriptomic mechanism whereby YBX1 drives HCC malignancy through m5C-dependent RNF115 stabilization, highlighting this axis as a promising therapeutic target.**摘要**本研究通过全转录组分析发现，肝细胞癌（hepatocellular carcinoma, HCC）组织中5-甲基胞嘧啶（m5C）修饰模式存在显著异质性，差异甲基化基因广泛分布于除Y染色体外的全基因组范围内。5-甲基胞嘧啶阅读蛋白YBX1在HCC组织中显著上调，且与不良预后密切相关。本研究整合m5C甲基化RNA免疫沉淀测序（methylated RNA immunoprecipitation sequencing, MeRIP-seq）与YBX1 RNA免疫沉淀测序（RNA immunoprecipitation sequencing, RIP-seq）数据，鉴定出RNF115是受YBX1直接调控且依赖m5C修饰的靶基因。机制研究显示，YBX1可结合RNF115信使RNA（mRNA）3'非翻译区（3' untranslated region, 3'UTR）内的m5C修饰基序，进而增强其稳定性与翻译效率。RNF115过表达与肿瘤晚期分期、转移率升高及不良临床结局显著相关。进一步研究表明，YBX1/m5C-RNF115信号轴主要通过激活磷脂酰肌醇3-激酶/蛋白激酶B（phosphatidylinositol 3-kinase/protein kinase B, PI3K/AKT）通路促进HCC进展。本研究揭示了一种全新的表观转录组学调控机制：YBX1通过依赖m5C修饰的RNF115稳定化途径驱动HCC恶性进展，提示该信号轴可作为极具潜力的治疗靶点。