(Press-News.org) Metabolic Syndrome (MetS), characterized by abdominal obesity, hypertension, dyslipidemia, and insulin resistance, represents a global health crisis with escalating prevalence. Its comorbidities—including type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), atherosclerosis, and polycystic ovary syndrome (PCOS)—share underlying molecular pathways. Among these, the receptor for advanced glycation end products (RAGE) and its ligands (AGEs, HMGB1, S100 proteins) form the AGE/RAGE axis, a key driver of inflammation, oxidative stress, and tissue damage in MetS. While targeting this axis is a promising therapeutic strategy, the role of microRNAs (miRNAs) in its dysregulation remains poorly understood. This review systematically maps miRNA-mediated dysregulation of the AGE/RAGE pathway in MetS, employing a novel dual-method approach to overcome limitations of conventional literature reviews.
Methodology: Dual Analytical Approaches
Inductive ("Bottom-Up") Approach:
A classical literature review identified miRNAs targeting core AGE/RAGE genes (HMGB1, AGER, scavenger receptors) in MetS comorbidities.
Searches used PubMed queries combining gene names, "miRNA," and pathology terms (e.g., "atherosclerosis").
Limitation: Data were sparse, heavily skewed toward atherosclerosis (14/19 studies), and neglected key receptors (e.g., AGER, anti-RAGEs) and ligands (S100s).
Deductive/Synthetic ("Top-Down") Approach:
Step 1: Identified differentially expressed miRNAs (DEMs) from microarray studies across MetS comorbidities (obesity, T2DM, NAFLD, atherosclerosis, PCOS, periodontitis) in pathology-relevant tissues (e.g., liver for NAFLD, subcutaneous adipose tissue (sWAT) for obesity).
Step 2: Mapped DEMs to experimentally verified targets in miRTarBase v9.0.
Step 3: Overlapped targets with an extended AGE/RAGE pathway gene set (from WikiPathways WP2324 + key receptors/ligands).
Innovation: Enabled ranking of comorbidities by degree of AGE/RAGE dysregulation and discovery of novel miRNA-pathway connections.
Key Findings
Pathway Dysregulation Extends Beyond Atherosclerosis:
Atherosclerosis plaques showed the highest miRNA-AGE/RAGE dysregulation (64 DEMs, 284 miRNA-target interactions (MTIs)), followed by MetS in peripheral blood mononuclear cells (PBMCs) and obesity in sWAT.
Significant dysregulation was also confirmed in immune cells (PBMCs) and adipose tissue, broadening the focus beyond vascular pathology.
Novel Multi-Pathology miRNAs:
miR-92a-3p (downregulated in obesity/sWAT, atherosclerosis, PCOS) targeted 13 AGE/RAGE genes (ADAM10, HMGB1, NFKB1), potentially linking adipose dysfunction, vascular injury, and PCOS.
miR-34a-5p (upregulated in PBMCs and plaques) regulated 15 pathway genes (HMGB1, NFKB1, STAT1) and promotes inflammation.
miR-145-5p/miR-143-3p (downregulated in obesity/sWAT and insulin resistance) jointly targeted 19 genes (AKT1, CD36, STAT3), implicating AGE/RAGE in adipose insulin signaling.
Critical Knowledge Gaps:
Core receptors (AGER, DDOST) and ligands (S100A6, S100A12, S100P) had <10 experimentally verified MTIs in databases, hindering analysis.
AGER itself had only 3 known MTIs, yet 67% were dysregulated in MetS comorbidities, underscoring its understudied role.
Validation Across Approaches:
8 miRNAs (e.g., miR-126-3p, miR-185-5p, let-7g-5p) identified via the inductive approach were validated as DEMs in the deductive analysis, confirming their roles in AGE/RAGE dysregulation across pathologies.
Clinical and Therapeutic Implications
Diagnostic Potential: DEMs like miR-92a-3p may serve as multi-comorbidity biomarkers.
Therapeutic Targets:
miR-145-5p overexpression reduced atherosclerosis in mice.
miR-34a-5p inhibition improved NAFLD in animal models.
miR-92a-3p antagonism attenuated atherosclerosis and reduced androgen synthesis in PCOS models.
Caveat: No studies directly link miRNA therapies to AGE/RAGE modulation in MetS, highlighting a research gap.
Conclusion
This review pioneers a synthetic strategy integrating miRNA profiling with pathway analysis, revealing widespread but understudied miRNA dysregulation of the AGE/RAGE axis in MetS. While atherosclerosis remains the best-characterized comorbidity, the approach uncovers significant dysregulation in adipose tissue, liver, and immune cells. Prioritizing poorly studied receptors (e.g., AGER, anti-RAGEs) and multi-pathology miRNAs (e.g., miR-92a-3p) could accelerate targeted therapies for MetS and its comorbidities.
Full text
https://www.xiahepublishing.com/1555-3884/GE-2025-00039
The study was recently published in the Gene Expression.
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