Lysine Acetylation as a Regulatory Mechanism in Cardiometabolic Disease: A Focus on Sirtuins

Protein lysine acetylation is a widespread post-translational modification that regulates metabolic enzyme activity and cellular function. Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases that act as key metabolic sensors coupling cellular energy status to the regulation of protein acetylation. Dysregulation of sirtuin activity, particularly sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), has been implicated in the pathogenesis of cardiometabolic diseases, including obesity, type 2 diabetes, cardiovascular disease and metabolic dysfunction-associated steatotic liver disease. Under conditions of nutrient excess, alterations in acetyl-coenzyme A (acetyl-CoA) and NAD+ availability promote mitochondrial protein hyperacetylation, contributing to impaired mitochondrial respiration. Evidence from genetic and proteomic studies across metabolically active tissues such as the liver, heart, adipose tissue, skeletal muscle and pancreatic b-cells, highlight a central role for sirtuins in maintaining metabolic homeostasis. Therapeutic strategies aimed at improving mitochondrial function through activation of sirtuins have gained significant attention. Early studies focused on natural sirtuin activators, such as resveratrol and honokiol, while subsequent efforts led to the development of synthetic small-molecule activators, although their mechanisms of action remain debated. More recently, small molecule activators of SIRT1, such as SRT2104, and SIRT3, such as 2-acetyl-4-phenylquinoline (2-AQPC) and SZC-6 have been identified. In parallel, NAD+ augmenting through supplementation of NAD+ precursors such as nicotinamide riboside and nicotinamide mononucleotide has shown similar promising metabolic benefits in preclinical rodent models. Sirtuin-mediated lysine deacetylation represents a central mechanism regulating metabolic function and a promising target for therapeutic intervention in cardiometabolic disease.