The Protein Acetylation Rheostat: Linking Autophagy and Senescence in Metabolic Disease

Metabolic diseases, such as obesity, type 2 diabetes (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), emerge from chronic nutrient overload that progressively disrupts cellular homeostasis and precipitates persistent inflammatory remodeling. Two stress-adaptive programs sit at the center of such pathological transition: autophagy, the homeostatic engine responsible for lysosomal recycling and organelle quality control, and cellular senescence, a tissue repair system that becomes deleterious when persistent, driving dysfunction through stable growth arrest and senescence-associated secretory phenotype (SASP)-associated inflammatory remodeling. Emerging evidence identifies lysine acetylation as a nutrient-sensitive molecular rheostat that orchestrates the reciprocal regulation of these two processes across metabolic tissues. Because acetylation dynamics are governed by the availability of acetyl-CoA and the NAD⁺-dependent deacetylation capacity of sirtuins, metabolic stress reshapes the enzymatic balance between acetyltransferases (KATs, e.g., p300/CBP) and deacetylases. This shift triggers a “double blow” to cellular health; the simultaneous suppression of autophagic flux and the epigenetic stabilization of senescent state. This review synthesizes mechanistic evidence showing how acetylation inhibits autophagy at multiple checkpoints, ranging from the activity of core autophagy proteins to lysosomal biogenesis, while concurrently reinforcing senescence through chromatin hyperacetylation and the activation of non-histone effectors such as NF-κB, p53 and FOXO proteins. We place particular emphasis on the mTORC1-p300-SIRT1 axis as the primary integration hub coupling nutrient status to this dual regulation. Finally, we discuss tissue-specific manifestations in the liver, adipose tissue, and other metabolic organs and highlight emerging therapeutic strategies, such as KAT inhibition/sirtuin activation, aimed at restoring the acetylation rheostat to improve autophagic competence while restraining senescence-driven metabolic decline.