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AIMS Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellular-signal regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS. METHODS AND RESULTS Eight-week-old MFS (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for four weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of elastin fragmentation by matrix metalloproteinase 2, apoptosis and collagen deposition. Critically, the therapeutic efficacy of NO2-OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1C1041G/+mice challenged with Angiotensin II. CONCLUSION NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-mediating pathways, thereby meriting further investigation into its application as a therapeutic agent for the treatment of this condition. TRANSLATIONAL PERSPECTIVE Thoracic aortic aneurysm formation is the major life-threatening complication of Marfan syndrome, a relatively common genetic connective tissue disorder. Although various potential therapeutic targets have been identified, specific pharmacological treatment options are still unavailable. In this study, we demonstrate that Nitro-oleic acid reduces ascending aortic elastin fragmentation, apoptosis, and fibrotic remodelling in Marfan syndrome through inhibition of extracellular-signal regulated kinases 1/2, Smad2 as well as nuclear factor kappa B overactivation and thereby mitigates aneurysm formation. Thus, Nitro-oleic acid, which has been developed as an oral compound, emerges as a potential treatment option for Marfan-related aortic disease.