Objective:Phenotypic　transformation　of　adventitial　fibroblasts　is　important　in　the　pathogenesis　of　hypertension.　This　study　was　designed　to　determine　whether　fibronectin　type　III　domain　containing　5　(FNDC5)　alleviates　the　phenotypic　transformation　of　adventitial　fibroblasts　in　hypertension　and　the　underlying　mechanisms.Methods　and　results:Experiments　were　carried　out　in　spontaneously　hypertensive　rats　(SHR)　and　Wistar-Kyoto　rats　(WKY)　and　primary　aortic　adventitial　fibroblasts.　FNDC5　was　downregulated　and　NLRP3　inflammasome　was　activated　in　aortic　adventitia　of　SHR.　FNDC5　overexpression　attenuated　adventitial　fibroblasts　phenotypic　transformation,　excessive　synthesis　and　secretion　of　matrix　components,　NLRP3　inflammasome　activation　and　inflammation　in　adventitial　fibroblasts　from　SHR.　Moreover,　FNDC5　overexpression　reduced　NADPH　oxidase　2　(NOX2)　expression　and　reactive　oxygen　species　(ROS)　production　in　adventitial　fibroblasts　from　SHR.　Similarly,　exogenous　FNDC5　inhibited　adventitial　fibroblasts　phenotypic　transformation,　expression　of　matrix　components,　NLRP3　inflammasome　activation　and　NOX2　expression　in　adventitial　fibroblasts　from　SHR.　FNDC5　overexpression　in　rats　attenuated　phenotypic　transformation,　inflammation　and　reactive　oxygen　species　(ROS)　production　in　the　aortic　adventitia　of　SHR.　Furthermore,　FNDC5　overexpression　reduced　blood　pressure　and　alleviated　vascular　remodeling　in　SHR.Conclusion:FNDC5　reduces　NOX2-derived　ROS　production,　NLRP3　inflammasome　activation　and　phenotypic　transformation　in　adventitial　fibroblasts　of　SHR.　FNDC5　plays　a　beneficial　role　in　attenuating　vascular　inflammation,　vascular　remodeling　and　hypertension　in　SHR.