Front Mol Biosci. 2026 Apr 22;13:1813285. doi: 10.3389/fmolb.2026.1813285. eCollection 2026.
ABSTRACT
MicroRNAs (miRNAs) are key post-transcriptional regulators that orchestrate complex gene regulatory networks controlling endothelial function, metabolic adaptation, inflammation, and tissue remodeling. Among them, miR-126-3p, miR-126-5p, and miR-423-5p have emerged as context-dependent modulators linking vascular biology with cardiometabolic and oncologic disorders. MiR-126, through its 3p and 5p strands, plays a central role in maintaining endothelial integrity and angiogenic homeostasis. By modulating phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase (MAPK), and inflammatory signaling pathways, miR-126 regulates vascular repair, endothelial activation, and immune-vascular interactions. Reduced miR-126 expression is consistently associated with endothelial dysfunction, impaired angiogenic balance, and disease progression in diabetes, chronic kidney disease, and multiple cancers. In parallel, miR-423-5p regulates oxidative stress responses, transforming growth factor beta (TGF-β)-related pathways, and PI3K/AKT signaling in a context-dependent manner. Through modulation of redox balance, fibrotic remodeling, and cell survival pathways, miR-423-5p may exert either tumor-suppressive or pro-tumorigenic effects depending on cellular and microenvironmental conditions. In cardiometabolic and renal disorders, it contributes to microvascular dysfunction and inflammatory activation while also demonstrating translational potential as a circulating biomarker candidate. This review synthesizes shared and divergent signaling mechanisms governed by these miRNAs across disease states, emphasizing strand selection, target competition, and network-level cross-talk as determinants of context-specific outcomes. Understanding these multilayered regulatory interactions may support the development of network-oriented biomarker panels and precision RNA-based therapeutic strategies.
PMID:42100367 | PMC:PMC13143781 | DOI:10.3389/fmolb.2026.1813285