Sarcopenia, characterized by progressive muscle loss and weakness, is a major contributor to frailty and poor outcomes in aging populations. Chronic inflammation and malnutrition often coexist in older adults, jointly driving metabolic dysregulation and muscle atrophy—a process conceptualized as the Inflammation–Nutrition–Sarcopenia Axis (INSA). This study aimed to elucidate the molecular mechanisms of INSA by identifying stable miRNA–mRNA regulatory networks that bridge inflammation, nutrition, and muscle metabolism. Twelve public miRNA expression datasets encompassing chronic inflammatory diseases, malnutrition, and sarcopenia were integrated using a dual-axis Robust Rank Aggregation (RRA) approach. Seventeen consistent and seventy stable miRNAs were identified across datasets. High-confidence target genes were predicted through multi-database validation (miRTarBase, TarBase, TargetScan) and analyzed via protein–protein interaction (PPI) and enrichment analyses. The resulting network revealed key signaling pathways—PI3K/AKT, mTOR, AMPK, and FOXO—forming a convergent regulatory framework linking catabolic activation, energy imbalance, and impaired muscle regeneration. Hub genes such as TP53, MTOR, and FOXO3 emerged as central mediators of apoptosis and proteolysis. These findings define the molecular landscape of INSA and provide mechanistic insight into sarcopenia pathogenesis, highlighting potential circulating miRNAs as biomarkers and therapeutic targets for early intervention in multimorbid older adults.

miRNA, Sarcopenia, Inflammation, Malnutrition, PI3K/AKT, mTOR, FOXO, Bioinformatics