Hypertension-associated end-organ damage commonly leads to cardiac and renal fibrosis. As no effective anti-fibrotic therapy currently exists， the unchecked progression of fibrogenesis manifests as cardio-renal failure and early death. We have previously shown that FATp300-p300 with intrinsic factor acetyltransferase activity-is an essential epigenetic regulator of fibrogenesis， and is elevated in several fibrotic tissues. In this report， we investigate the therapeutic efficacy of a novel FATp300 inhibitor， L002， in a murine model of hypertensive cardio-renal fibrosis. Additionally， we examine the effects of L002 on cellular pro-fibrogenic processes and provide mechanistic insights into its antifibrogenic action. Utilizing cardiac fibroblasts， podocytes， and mesangial cells， we demonstrate that L002 blunts FATp300-mediated acetylation of specific histones. Further， incubating cells with L002 suppresses several pro-fibrogenic processes including cellular proliferation， migration， myofibroblast differentiation and collagen synthesis. Importantly， systemic administration of L002 in mice reduces hypertension-associated pathological hypertrophy， cardiac fibrosis and renal fibrosis. The anti-hypertrophic and anti-fibrotic effects of L002 were independent of blood pressure regulation. Our work solidifies the role of epigenetic regulator FATp300 in fibrogenesis and establishes it as a pharmacological target for reducing pathological matrix remodeling and associated pathologies. Additionally， we discover a new therapeutic role of L002， as it ameliorates hypertension-induced cardio-renal fibrosis and antagonizes pro-fibrogenic responses in fibroblasts， podocytes and mesangial cells.