MicroRNA-phytochemical interactome targeting thioredoxin-interacting protein: a narrative review at the nexus of RNA therapeutics, cancer biology, and metabolic regulation

Abstract

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.