Background/Objectives: The rising global prevalence of metabolic diseases (e.g., obesity, type 2 diabetes mellitus) underscores the need for effective interventions. Omega-3 polyunsaturated fatty acids (PUFAs) exhibit therapeutic potential, yet their molecular mechanisms remain unclear. This systematic review synthesizes a decade (2014-2024) of omics research to elucidate Omega-3 PUFA mechanisms in metabolic diseases and identify future directions. Methods: A PRISMA-guided search of the Web of Science identified studies on Omega-3 PUFAs, metabolic diseases, and omics. After excluding reviews, non-English articles, and irrelevant studies, 72 articles were analyzed (16 multi-omics, 17 lipidomics, 10 transcriptomics/metabolomics/microbiomics each, and 6 proteomics). Results: Omics studies demonstrated that Omega-3 PUFAs, particularly EPA and DHA, improve metabolic health through interconnected mechanisms. They regulate epigenetic processes, including DNA methylation and miRNA expression, influencing genes linked to inflammation and insulin sensitivity. Omega-3 PUFAs reduce oxidative stress by mitigating protein carbonylation and enhancing antioxidant defenses. Gut microbiota modulation is evident through increased beneficial taxa (e.g., Bacteroidetes, Akkermansia) and reduced pro-inflammatory species, correlating with improved metabolic parameters. Mitochondrial function is enhanced via upregulated fatty acid oxidation and TCA cycle activity, while anti-inflammatory effects arise from NF-κB pathway suppression and macrophage polarization toward an M2 phenotype. Challenges include interindividual variability in responses and a limited understanding of dynamic metabolic interactions. Conclusions: Omega-3 PUFAs target multiple pathways to improve metabolic health. Future research should prioritize chemoproteomics for direct target identification, multi-omics integration, and personalized strategies combining Omega-3 with therapies like calorie restriction.
Keywords: metabolic diseases; omega-3 polyunsaturated fatty acids; omics.