Arachidonic acid intake promotes hypertension and target-organ fibrosis through CYP4A-mediated 20-HETE overproduction: Integrated evidence from human and animal studies

The unregulated use of highly purified arachidonic acid (AA) supplements among Chinese fitness enthusiasts raises concerns about cardiovascular safety. To evaluate these risks, we integrated population-based, genetic, and experimental evidence. Cross-sectional analysis of NHANES data demonstrated a higher risk of hypertension in individuals within the highest AA intake quartile (OR = 1.262, 95% CI: 1.109-1.438, <i>P</i> < 0.001). Two-sample Mendelian randomization confirmed causal effects of AA metabolites, including thromboxane (OR = 1.006, <i>P</i> < 0.001), eicosanoid C20H28O4 (OR = 1.305, <i>P</i> = 0.009), and 20-HETE-related C20H32O3 (OR = 1.290, <i>P</i> = 0.043). Single-cell transcriptomic profiling revealed increased renal expression of CYP4A11 in hypertensive patients, supporting a mechanistic link between AA metabolism and blood pressure regulation. In vivo, Wistar-Kyoto and spontaneously hypertensive rats fed a high-dose AA diet for six weeks exhibited significant elevations in systolic, diastolic, and mean arterial pressure, accompanied by increased renal vascular resistance. Mechanistic analyses showed that AA upregulated CYP4A1 expression and enhanced 20-HETE production without altering thromboxane synthase activity. Histological assessments revealed glomerular edema, tubular injury, and marked cardiac and renal fibrosis in AA-treated animals. Together, these convergent findings indicate that chronic high-dose AA intake promotes hypertension and multiorgan fibrosis via CYP4A/20-HETE activation. These results highlight the translational importance of AA metabolism in cardiovascular disease and underscore the need for regulatory oversight of AA supplements and therapeutic targeting of this pathway.