The Impact of Omega Fatty Acids on <scp>DKD</scp> : A Multimodal Study Integrating Mendelian Randomization, Proteomic Mediation Analysis, and Meta‐Analysis

Diabetic kidney disease (DKD), a significant microvascular complication of diabetes, is escalating the global disease burden. Research suggests free fatty acids, particularly specific polyunsaturated fatty acids, may influence DKD development and progression through anti-inflammatory and antioxidant mechanisms. However, existing evidence remains controversial, and the precise underlying mechanisms are still unclear. We performed a two-sample Mendelian randomization (MR) analysis leveraging genome-wide association study data and plasma proteomic panels. A two-step protein-mediated MR framework and Reactome pathway enrichment were employed to identify mediators and elucidate biological pathways. Subsequently, we conducted a meta-analysis of clinical studies to comprehensively evaluate the impact of omega-3 supplementation on DKD patients. Genetically predicted higher plasma omega-3 fatty acid levels were causally associated with reduced DKD risk (odds ratio [OR] = 0.869, 95% confidence interval [CI]: 0.772-0.978, p = 0.020), while omega-6 fatty acids showed no significant causal association (OR = 0.895, 95% CI: 0.731-1.096, p = 0.283). Fourteen plasma proteins showed nominally significant evidence of partial mediation, with consistent mediation directions and mediation proportions ranging from 2.10% to 29.80%. Potential mediators included neuronal pentraxin-2, hemoglobin subunit theta-1, and periostin. Enrichment analysis highlighted Notch signaling, apoptosis regulation, and chronic inflammatory pathways as core processes. Meta-analysis of 12 randomized controlled trials (474 participants) showed that omega-3 supplementation significantly reduced triglycerides (mean difference [MD] = -0.27 mmol/L, 95% CI: -0.35 to -0.20, p < 0.00001), systolic blood pressure (MD = -4.50 mmHg, 95% CI: -7.57 to -1.42, p = 0.004), and kidney injury molecule-1 (MD = -1.74 pg/mL, 95% CI: -2.58 to -0.89, p < 0.0001), while increasing high-density lipoprotein cholesterol (MD = 0.14 mmol/L, 95% CI: 0.04-0.23, p = 0.004). No significant improvements in albumin-to-creatinine ratio or estimated glomerular filtration rate were observed. Genetic evidence demonstrates that elevated omega-3 fatty acid levels may causally reduce DKD risk, with this protective effect possibly partially mediated by plasma proteins. The meta-analysis findings confirm that omega-3 supplementation effectively ameliorates lipid profiles, systolic blood pressure, and early renal impairment in DKD cases. Dietary omega-3 supplementation may offer a protective effect against DKD, though this association requires further validation.