METTL3-mediated mA modification of pri-miR-93 promotes hepatocellular carcinoma progression via CDKN1A suppression.

N6-methyladenosine (mA) is the most common RNA modification in eukaryotic transcriptomes and plays a key role in various biological processes. However, its function in disease, particularly in microRNA regulation, remains unclear. Hepatocellular carcinoma (HCC) is a major global health challenge, with high morbidity and mortality rates. Investigating the role of mA modification in HCC may provide valuable insights into its molecular mechanisms. This study found that METTL3, an mA methyltransferase, is significantly upregulated in HCC and is associated with poor prognosis. Bioinformatics analysis of the GSE37001 dataset showed that silencing METTL3 in HepG2 cells suppressed cell cycle-related pathways. Among several candidate miRNAs potentially regulated by METTL3 in an mA-dependent manner, miR-93-5p was selected for further study. Experimental results demonstrated that METTL3-mediated mA modification promotes miR-93-5p expression by facilitating pri-miR-93 processing. Functional assays confirmed that miR-93-5p directly targets CDKN1A and downregulates its expression. Moreover, METTL3 overexpression rescued the effects of METTL3 knockdown on pri-miR-93 mA levels and miR-93-5p expression. Rescue experiments further showed that METTL3 promotes HCC cell proliferation and cell cycle progression while inhibiting apoptosis via the miR-93-5p/CDKN1A axis. In summary, METTL3 is highly expressed in HCC and contributes to tumor progression by promoting miR-93-5p expression through mA modification, thereby suppressing CDKN1A. These findings highlight a potential regulatory mechanism in HCC and suggest that targeting the METTL3/miR-93-5p/CDKN1A axis could be a novel therapeutic strategy.