New insights into the ACLY-mediated metabolic and epigenetic interplay in macrophages

Macrophages are plastic innate immune cells that polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes in response to microenvironmental signals, with their dynamic balance governing inflammation resolution and tissue homeostasis. This polarization entails profound metabolic reprogramming, wherein ATP-citrate lyase (ACLY) acts as a key regulator. By controlling intracellular acetyl-CoA production, ACLY modulates histone acetylation and chromatin remodeling, thereby influencing the expression of inflammation-related genes. This review systematically outlines ACLY's structural features and elucidates its core mechanisms that integrate metabolic and epigenetic cues to orchestrate macrophage polarization and inflammatory responses. In addition, it summarizes the pharmacological properties and clinical translational potential of ACLY inhibitors, highlighting their promise as therapeutic agents. Collectively, this work aims to offer novel theoretical insights and intervention strategies for targeting macrophage immunometabolism in chronic inflammation and associated metabolic disorders.