Background and aims: Excessive intake of fructose is a significant contributor in the development of hypertension and pathogenesis of cardiometabolic diseases. We previously showed that dietary inulin can prevent fructose-induced hypertension in rats. Nevertheless, mo-lecular mechanisms of both fructose and inulin in aorta remain unknown. The aim of this study was to identify global transcriptomic changes in aorta in rats on fructose-based diet or partial substitution of dietary fructose with inulin.Methods and results: At the end of study periods, aortas were isolated, RNA extracted, and tran-scriptomics performed using microarrays followed by in-dept bioinformatic analyses. We observed that fructose-based diet affected the expression of over 1700 genes involved in the regulation of vascular functions, cell signaling, and cellular metabolism. Partial substitution of di-etary fructose with inulin affected the expression of over 1300 genes regulating endothelial and vascular functions, including relaxin signaling pathway, immune/inflammatory response, or cellular metabolism. Bioinformatic analyses revealed transcription factors, such as Junb or Nr4a2, and miRNAs, such as miR-206, miR-137 or miR-375, as potential transcriptional and post-transcriptional regulators of identified differentially expressed genes. Genes identified following both diets are associated with development of cardiovascular diseases, hypertension, immune system diseases and metabolic diseases. Moreover, a negative correlation between the expression profiles obtained by fructose-based diet and that by partial substitution of dietary fructose with inulin was observed.Conclusion: Our study showed that fructose can significantly impact global transcriptomic profile in aorta, changes that can be counteracted by inulin and which present relevant molecular mech-anisms underlying its anti-hypertensive property.& COPY; 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Ital-ian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.