ATP-citrate lyase is a critical regulator of physiological and pathological angiogenesis

Sprouting angiogenesis requires endothelial cells (ECs) to transition into specialized tip and stalk cells, a process influenced by metabolic regulation. ATP-citrate lyase (ACLY), which generates acetyl-CoA from citrate, is markedly activated in proliferating ECs (PECs) but less so in quiescent ECs (QECs). However, it remains elusive whether ACLY-derived acetyl-CoA fuels angiogenesis. Here, we demonstrate the critical role of ACLY in angiogenesis. ACLY depletion impaired EC proliferation, migration, tube formation, and sprouting, while EC-specific Acly-knockout mice showed reduced physiological and pathological angiogenesis, including in oxygen-induced retinopathy (OIR). Mechanistically, ACLY fuels glycolysis, boosts acetyl-CoA production, and enhances histone acetylation at key angiogenic gene loci. Intriguingly, acetate supplementation restored acetyl-CoA levels and rescued defective angiogenesis in ACLY-deficient models. In addition, pharmacological inhibition of ACLY suppressed neovascularization in OIR models. These findings establish ACLY as a previously unrecognized metabolic and epigenetic regulator of angiogenesis, highlighting its potential as a therapeutic target for pathological neovascularization.