Front Immunol. 2026 ;17
1784874
Atherosclerosis (AS) is the leading cause of cardiovascular disease-related mortality worldwide and serves as the core pathological basis for cardiovascular events. Protein acetylation, a widespread and highly dynamic post-translational modification, has emerged as a critical link connecting epigenetic regulation, metabolic homeostasis, and inflammatory signaling, thereby playing an important role in both the initiation and progression of AS. This review systematically summarizes the major forms of protein acetylation, including N-terminal acetylation and lysine acetylation, as well as the key regulatory enzymes involved, such as acetyltransferases (e.g., HATs and NATs) and deacetylases (e.g., HDACs and sirtuins). Particular emphasis is placed on the cell type-specific regulatory roles of acetylation in macrophages, vascular endothelial cells, and vascular smooth muscle cells. Accumulating evidence indicates that protein acetylation modulates gene transcription and protein function through multiple mechanisms, thereby influencing a broad spectrum of AS-related processes, including inflammation, glycolipid metabolism, oxidative stress, energy metabolism, apoptosis, proliferation, and migration. Based on these mechanisms, therapeutic strategies targeting enzymes that regulate acetylation, particularly selective HDAC inhibitors and sirtuin activators, have emerged as promising approaches for the treatment of AS. By integrating recent advances in cellular heterogeneity, plaque stage-specific regulation, and human translational evidence, this review further discusses the therapeutic potential of targeting acetylation-regulating enzymes and critically evaluates the current limitations of this strategy, including contradictory findings, off-target effects, and barriers to clinical translation. Overall, protein acetylation represents a key regulatory hub linking epigenetics, metabolism, and inflammation. A deeper understanding of its regulatory network may provide new insights into the development of precision therapies for AS.
Keywords: atherosclerosis; inflammatory response; protein acetylation; protein acetyltransferases; protein deacetylases