MicroRNAs in thoracic aortic aneurysm: From biomarkers to therapeutic targets

Abstract

Introduction: Thoracic aortic aneurysm (TAA) is a life-threatening aortic disease often referred to as a “silent killer” because it progresses insidiously until reaching a critical stage, when aortic dissection or rupture may occur. The pathophysiology of TAA involves complex and dysregulated interactions between vascular smooth muscle cells (VSMCs) and the extracellular matrix (ECM), driven by genetic mutations, mechanical stress, inflammatory responses, and oxidative stress. However, the causal relationships and molecular links among these processes remain incompletely understood. Recently, microRNAs (miRNAs), a class of endogenous non-coding RNAs of approximately 22 nucleotides that regulate gene expression, have attracted increasing attention in TAA because of their remarkable stability, tissue specificity, and regulatory versatility, as well as their potential roles in both disease pathogenesis and biomarker development. Methods: A systematic literature search was conducted across Web of Science, PubMed, and other relevant databases using keywords related to TAA, microRNAs, VSMCs, ECM remodeling, pathogenesis, and biomarker. The retrieved studies were synthesized to examine miRNA-mediated regulation of VSMC dysfunction and ECM remodeling as a central mechanistic framework for TAA initiation and progression, while also integrating upstream drivers such as genetic alterations and mechanical stress, as well as modulatory processes including inflammation, oxidative stress, and endothelial-to-mesenchymal transition (EndMT). The translational potential of miRNAs as biomarkers and therapeutic targets, together with the key challenges to their clinical application, was also evaluated. Results: Current evidence indicates that miRNAs act as critical molecular regulators linking upstream pathogenic drivers, including genetic abnormalities and mechanical stress, to key downstream processes such as VSMC dysfunction, ECM remodeling, inflammation, oxidative stress, and EndMT. These interconnected mechanisms do not operate independently but rather interact and reinforce one another, thereby promoting aneurysm initiation and progression. In addition, a growing body of evidence suggests that TAA-related miRNAs may serve as promising biomarkers for early diagnosis and prognostic assessment, while also representing potential therapeutic targets. Conclusions: This review highlights the multifaceted roles of miRNAs in TAA and supports their value as an integrative framework for understanding disease pathogenesis. Although miRNAs show considerable promise as biomarkers and therapeutic targets, their clinical translation remains limited by heterogeneity, lack of standardization, and insufficient large-scale validation. Future efforts should focus on multicenter validation and integration with imaging and clinical data to advance the use of miRNAs in precision diagnosis and management of TAA.