THERAPEUTIC POTENTIAL OF MIRNA-BASED REGULATION IN METABOLIC DISEASES: AN INTEGRATIVE NETWORK BIOLOGY APPROACH LINKING LIVER AND PANCREATIC DYSFUNCTION

Abstract

Non-alcoholic fatty liver disease, Type 2 diabetes mellitus and dyslipidemia share common pathological mechanisms including chronic inflammation, insulin resistance, extracellular matrix remodeling, and endothelial dysfunction. However, the integrated molecular signatures that link these conditions remain incompletely defined. An integrated systems and computational biology method to identify common molecular markers among different metabolic diseases. To identify shared hub genes, liver and pancreatic gene data were subjected to tissue-specific gene co-expression assessment, followed by construction of gene miRNA and transcription factor regulatory networks using NetworkAnalyst. ICAM1 and COL3A1 were identified as key hub genes commonly dysregulated in both liver and pancreatic tissues, implicating their respective roles in inflammatory and fibrotic processes. Gene-miRNA network analysis identified miR-335-5p and the miR-26b-5p as central regulators based on node degree filtering. Across NAFLD, T2DM, and dyslipidemia, a reciprocal pattern of dysregulation was observed, characterized by consistent upregulation of hsa-miR-335-5p and downregulation of hsa-miR-26b-5p. Transcription factor-gene interaction analysis further identified RELA, NFKB1, and SP1 as key transcriptional regulators, with NFKB1 and RELA influencing ICAM1 expression and SP1 regulating COL3A1 expression. The successful clinical translation of RNA interference therapeutics including inclisiran, patisiran, and givosiran has established the feasibility of oligonucleotide based strategies for metabolic diseases. Based on the network analyses conducted, a combination therapy comprising antagomiR-335-5p and miR-26b-5p mimic is proposed as a rational treatment strategy, given the dual mechanism of action involving inhibition of pathogenic miR-335-5p alongside restoration of physiological miR-26b-5p levels to indirectly normalize RELA/NFκB, SP1, ICAM1, and COL3A1 function. These results indicate that ICAM1, COL3A1, and their associated miRNAs may serve as promising novel biomarkers and therapeutic targets for the development of integrated therapies for metabolic diseases.