NSUN5 Facilitates Hepatocellular Carcinoma Progression by Increasing SMAD3 Expression

Abstract Hepatocellular carcinoma (HCC) is characterized by frequent intrahepatic and distant metastases, resulting in a poor prognosis for patients. Epithelial–mesenchymal transition (EMT) plays a pivotal role in this process. However, the expression of NOP2/Sun RNA methyltransferase 5 (NSUN5) in HCC and its role in mediating EMT remain poorly understood. In this study, clinicopathological analyses are conducted across multiple independent HCC cohorts and induced tumor formation in Nsun5‐knockout mice. The findings reveal an upregulation of NSUN5 expression in tumor tissues; conversely, the absence of Nsun5 hinders the malignant progression of HCC, indicating that NSUN5 may serve as a significant oncogene in HCC. Furthermore, elevated levels of NSUN5 enhance EMT processes within HCC cells. NSUN5‐knockout cells exhibit reduced invasion and migration capabilities under both in vivo and in vitro conditions, while overexpression of NSUN5 yields opposing effects. Mechanistically, high levels of NSUN5 promote the enrichment of trimethylated histone H3 at lysine 4 (H3K4me3) at the promoter region of SMAD3 through recruitment of the WDR5, thereby facilitating HCC metastasis via SMAD3‐mediated EMT pathways. Collectively, this study identifies NSUN5 as a novel driver of metastasis in HCC and provides a theoretical foundation for potential therapeutic strategies against this malignancy.