review · Frontiers in Oncology
MicroRNAs are essential regulators of gene expression, metabolic dysfunction, oxidative stress, and cancer development. Phytochemicals can modify microRNA activity, biogenesis, and stability through transcriptional, epigenetic, and post-transcriptional mechanisms. A major focus is the thioredoxin-interacting protein pathway, which is implicated in diabetes, metabolic dysfunction-associated fatty liver disease, cardiovascular disorders, and diverse cancers. Specific microRNAs regulated by plant compounds include miR-148b, miR-33a/b, miR-17-5p, miR-224, and miR-20a. Evidence suggests phytochemicals can allosterically modulate RNA motifs to alter microRNA conformation, stability, and silencing complex loading without disturbing normal base pairing. Computational tools, including molecular docking and RNA-specific molecular dynamics simulations, serve to analyse these interactions, offering a foundation for developing RNA-directed therapies.
Chronic illnesses like cancer, diabetes, and cardiovascular disorders share cellular mechanisms linked to oxidative stress and metabolic imbalance. By demonstrating how natural phytochemicals might regulate microRNAs that control these processes, this framework aids the search for targeted treatments. Understanding these RNA-ligand mechanisms supports the long-term design of precision therapies for complex chronic conditions.
This research outlines an early-stage discovery framework for developing RNA-targeted therapeutics from phytochemicals to treat cancer, metabolic disorders, and chronic inflammatory diseases. The prospective end users are preclinical pharmaceutical researchers and computational drug design teams employing molecular docking and dynamics simulations to screen lead compounds. Given the reliance on computational modelling and narrative synthesis, the work is at an exploratory stage and remains far from practical therapeutic application.
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MicroRNAs (miRNAs) are increasingly recognized as central regulators of gene expression, cellular adaptation, and disease progression. This is fundamentally reshaping current understanding of disease molecular pathogenesis and therapeutic intervention. Beyond their established roles in development and metabolism, miRNAs actively participate in oncogenesis, metabolic dysfunction, inflammation, and redox homeostasis. Emerging evidence shows that phytochemicals can modulate miRNA-mediated regulatory networks by influencing miRNA biogenesis, expression, stability, and functional activity through transcriptional, epigenetic, and post-transcriptional mechanisms. Among these pathways, the thioredoxin-interacting protein (TXNIP) axis has attracted considerable attention because of its critical involvement in oxidative stress, inflammation, metabolic reprogramming, apoptosis, and cancer-associated signalling. For instance, dysregulated TXNIP expression is strongly associated with metabolic dysfunction-associated fatty liver disease (MAFLD), diabetes, cardiovascular diseases, neurodegenerative disorders, and multiple cancers, making it an attractive therapeutic target. This narrative review discussed emerging trends on phytochemical-mediated regulation of TXNIP-associated miRNAs, including miR-148b, miR-33a/b, miR-17-5p, miR-224, and miR-20a. Particular emphasis was placed on the conserved miRNA seed region as the principal determinant of target recognition, while discussing the emerging hypothesis that phytochemicals may allosterically modulate structurally accessible RNA motifs to influence miRNA conformation, stability, RNA-induced silencing complex loading, and target accessibility without disrupting canonical Watson-Crick base pairing. We further discussed molecular docking, RNA-specific molecular dynamics simulations, and complementary structural validation approaches as emerging tools for investigating RNA-ligand interactions. Therefore, this review has provided a mechanistic and translational framework integrating RNA biology, redox signalling, and precision medicine to guide future development of RNA-targeted phytochemical therapeutics for cancer, metabolic disorders, and other chronic diseases.
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DOI: 10.3389/fonc.2026.1907571
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