The Enigma of Protein Succinylation in Diabetes.

Lysine succinylation is a dynamic post-translational modification that alters protein structure and function by adding a succinyl group to lysine residues. This review first presents current evidence on the discovery of lysine succinylation and its regulatory enzymes, and then focuses on its roles in diabetes and its complications. We summarize that succinylation is potentially governed by writers (HAT1), erasers (SIRT5), and readers (GAS41), linking metabolic state to signaling and epigenetic regulation. Dysregulation of succinylation is associated with mitochondrial dysfunction, oxidative stress, and insulin resistance in key metabolic tissues, including the pancreas, liver, kidney, and heart. However, most studies remain correlative, and mechanistic insights into site-specific modifications are limited. The identities of bona fide succinyltransferases and dedicated reader domains are still uncertain, and tissue-specific regulatory networks in diabetes require further exploration. By synthesizing these findings, this review aims to inspire scientists to explore the succinylome to deepen our understanding of diabetic pathophysiology and identify novel therapeutic strategies.