BACKGROUND: Recent studies show that hyperactivation of mTOR (mammalian target of rapamycin) signaling plays a causal role in the development of thoracic aortic aneurysm and dissection. Modulation of PP2A (protein phosphatase 2A) activity has been shown to be of significant therapeutic value. In light of the effects that PP2A can exert on the mTOR pathway, we hypothesized that PP2A activation by small-molecule activators of PP2A could mitigate AA progression in Marfan syndrome (MFS). METHODS: Two distinct mouse models of MFS underwent daily oral administration of small-molecule activators of the PP2A compound DT-061 to assess its therapeutic potential. Echocardiography was performed to monitor the growth of the aortic root and ascending aorta. Histological evaluation was performed to assess alterations in the vascular wall. RNA-sequencing, Western blot, and immunostaining were performed to decipher the underlying mechanisms by which DT-061 suppresses AA progression. RESULTS: PP2A activity decreased, while mTOR activity increased in both human and mouse aortas with MFS. Concordantly, oral administration of DT-061 increased PP2A activation, reducing aortic expansion in Marfan mice. DT-061 treatment also mitigated medial hypertrophy, elastin breakdown, and extracellular matrix deterioration in the ascending aorta, along with decreased metalloproteinase activities. Mechanistic studies suggest that DT-061 suppresses mTOR signaling and smooth muscle cell dedifferentiation, contributing to its effects on thoracic aortic aneurysm and dissection progression. CONCLUSIONS: These studies demonstrate a pathological role of PP2A activity loss in the cause of MFS and implicate that activation of PP2A may serve as a novel therapeutic strategy to limit MFS progression, including aortic aneurysm formation.