The relationship between plasma long-chain fatty acids and hypertension and its underlying molecular mechanisms

The associations between plasma long-chain fatty acids and hypertension remain incompletely understood, particularly in middle-aged and older adults, and the underlying mechanisms are still unclear. This study aimed to investigate the associations between plasma long-chain fatty acids and hypertension and to explore the underlying molecular mechanisms using an integrated network pharmacology and molecular docking approach. We included 2092 middle-aged and older adults with available measurements of plasma long-chain fatty acid concentrations. Stepwise adjusted logistic regression and Bayesian kernel machine regression were used to assess the associations of individual fatty acids and mixed fatty acid exposure with hypertension. Potential targets of fatty acids and hypertension were identified from public databases, followed by protein-protein interaction network construction, hub target identification, enrichment analyses, and molecular docking. After adjustment for sex, age, sociodemographic characteristics, lifestyle factors, and body mass index, myristoleic acid, arachidonic acid, erucic acid, and docosahexaenoic acid were inversely associated with hypertension, whereas eicosapentaenoic acid and docosatetraenoic acid were positively associated. Mixed-exposure analysis suggested a modest overall effect, with the main contributions arising from these key fatty acids. MAPK3, PTGS2, and ESR1 were identified as hub targets and were mainly involved in inflammation, immune responses, lipid metabolism, and vascular function. In conclusion, plasma long-chain fatty acid profiles were associated with hypertension in middle-aged and older adults and may provide new epidemiological evidence and mechanistic insights into hypertension risk.