Advances in Biology & Earth Sciences

Acetylation is a post-translational modification that alters protein function and plays a crucial role in regulating numerous cellular processes, especially metabolic flexibility, indicating the capacity of cells to modify their metabolic processes following changing energy demands and nutrient availability. Recent mechanistic advances have highlighted the role of mitochondrial sirtuins, such as SIRT3, in controlling acetyl-CoA pools for histone acetylation, directly affecting metabolic flexibility, particularly in the context of aging. Any change in acetylation and deacetylation state leads to the emergence of various metabolic disorders, including neurodegenerative diseases. Moreover, new reports underscore the crosstalk between acetylation and autophagy in the regulation of cancer metabolism, illustrating acetylation's broader regulatory roles. Modulating the activity of enzymes utilizing molecules with inhibitor and activator properties exhibits significant potential for clarifying the cellular functions of acetylation in metabolic sensing and developing therapeutics. This review discusses the enzymes, along with the mechanisms related to acetylation and metabolic flexibility and importantly, it highlights acetylation's influence on both proteostasis and autophagy. Pharmacological modulation of acetyltransferases and deacetylases through selective inhibitors and activators represents a promising therapeutic strategy for metabolic disorders, offering potential for precision medicine approaches. By combining current knowledge on acetylation-mediated metabolic regulation, critical gaps remain, such as the need to clarify sex-specific chromatin dynamics in acetylation. This review highlights critical gaps in understanding tissue-specific acetylation patterns and provides a framework for developing targeted interventions for treating complex metabolic diseases through modulation of the acetylation machinery.