Hepatocellular carcinoma (HCC) is one of the most highly aggressive and fatal malignancies. It ranks as the sixth most common tumor in the world and, more importantly, it occupies the third position among cancer-related deaths. Centella asiatica is a medicinal plant widely pharmacologically potent which may include anti-inflammatory, anticancer, hepatoprotective as well as wound healing activity. Increasing evidence supports cross-kingdom regulation for plant-origin microRNAs (miRNAs), delivered into host cells through dietary intake to regulate gene expression levels involved in pharmacological actions from medicinal plants. An in silico homologous miRNA screening method was applied to identify potential Centella asiatica miRNAs targeting HCC genes. Homologous miRNA sequences were first identified from the Centella asiatica genome with BLASTN, and their secondary structures were predicted with MFold server. Putative human targets were then predicted using psRNATarget and only those retained that could be cross-referenced with known HCC-associated genes. These targets were subjected to Gene Ontology and KEGG pathway analysis in Enrichr and DAVID, respectively. Protein-protein interaction (PPI) networks were then constructed in Cytoscape for hub gene identification using cytoNCA while survival and expression analyses were implemented in GEPIA2.49 C.asiatica miRNAs were identified with 63 target genes overlapping the HCC-associated gene set. CDKN1A, IRS1, MAPK14, SSB, and TARDBP were found as hub genes from PPI network analysis among the targets. Further filtering of these hubs through survival analysis revealed them as prognostic hubs possibly regulated by cai-miR393a and cai-miR156a. This is the first comprehensive study to predict that Centella asiatica-derived miRNA particularly cai-miR393a and cai-miR156a may play a role in HCC by targeting SSB and TARDBP. Therefore, results of the present study add a novel cross-kingdom regulatory mechanism and place Centella asiatica miRNAs as potential candidates for translational developments in HCC therapy.
Extracellular vesicles (EVs) are lipid bilayer nanoparticles secreted by almost all cell types, serving as vital mediators of intercellular communication by transporting bioactive cargos, including proteins, lipids, and nucleic acids. This review summarizes the emerging role of EVs as pivotal carriers in cancer epigenetic regulation, focusing on their functions in cancer pathogenesis through the delivery of non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), as well as the modulation of DNA methylation and histone modifications. Drawing on evidence from various malignancies (including osteosarcoma, breast cancer, gastric cancer, hepatocellular carcinoma, cervical cancer, lung cancer, pancreatic cancer, colorectal cancer, bladder cancer, and esophageal squamous cell carcinoma), we systematically elucidate how tumor- or matrix-derived EVs promote tumor progression by delivering specific epigenetic regulators (e.g., NORAD, miR-3190, and circ_0064516). These EV-encapsulated molecules can inhibit tumor suppressors, activate oncogenic pathways (such as PI3K/AKT and Wnt/β-catenin), and promote epithelial-mesenchymal transition, angiogenesis, immune evasion, and metastasis. Furthermore, EVs reshape the epigenetic landscape of the tumor microenvironment by inducing genomic DNA hypomethylation (e.g., LINE-1) and altering histone modifications. Finally, we discuss the potential of EV-associated epigenetic molecules as diagnostic biomarkers and therapeutic targets, underscoring the clinical significance of EVs as key information carriers in oncology.