Protein succinylation in disease: Mechanistic insights and therapeutic targeting

Protein lysine succinylation (Ksucc) has emerged as a significant post-translational modification with broad structural and functional implications in human diseases. This modification, characterized by the addition of a succinyl group to a lysine residue, markedly alters charge and steric bulk, thereby regulating diverse molecular processes spanning DNA regulation, RNA metabolism, and protein function. The dynamic balance of Ksucc is orchestrated by opposing actions of “writer” (succinyltransferases) and “eraser” (desuccinylases) enzymes. Critically, the dysregulation of Ksucc is increasingly implicated in the pathogenesis of a spectrum of diseases, including cancer, neurodegenerative disorders, and metabolic conditions. This review systematically delineates the molecular mechanisms of Ksucc and its disease-driving roles across different biological levels. Furthermore, we synthesize the current landscape of emerging therapeutic strategies, highlighting the development of small-molecule compounds targeting the Ksucc machinery. A deeper understanding of protein succinylation networks promises to unveil novel pathogenic mechanisms and pave the way for precision targeted therapies.