Pulmonary arterial hypertension (PAH) is a progressive occlusive vascular disease (OVD) in which pulmonary artery (PA) smooth muscle cells (PASMC) are characterized by excessive proliferation and resistance to apoptosis, like in cancer cells. These features are shared with neointimal hyperplasia in coronary artery disease (CAD). ATP citrate lyase (ACLY), has recently emerged in cancer as a key player to sustain cellular proliferation and survival by favoring Warburg effect, chromatin acetylation, and lipid synthesis. However, its role in OVD remains unknown. Thus, we hypothesized that ACLY is upregulated in OVD and supports the proliferative phenotype of OVD-SMCs. Increased expression and nuclear localization of ACLY were observed in 1) VRD-SMCs from both PAH and CAD patients compared to controls (immunoblot, IB; immunofluorescence, IF) and 2) in PAH and CAD rodents models (SugenHypoxia, SuHx and carotid injury, CI). ACLY inhibition impedes OVD-SMC bioenergetics and lipid metabolism (OCR/ECAR ratio, RNASeq) and decreased nuclear acetyl CoA, histones acetylation reducing SMC proliferation and survival (Ki67 and AnnexinV by IF, PCNA and Survivin by IB). In vivo, pharmacological inhibition of ACLY significantly improved pulmonary hemodynamics / remodeling in SuHx rats and neointimal hyperplasia in CI rats. Smooth muscle specific Acly K.O mice were resistant to both PAH and CI. In conclusion, we demonstrated that inhibition of ACLY may represent a novel and attractive therapeutic avenue for OVD. Both Y. Grobs and C. Romanet equally contributed