Post-Translational modifications and proteomic mechanisms underlying substance use disorder

Substance Use Disorder (SUD) is a chronic, relapsing condition driven by complex neurobiological changes, many of which are mediated by post-translational modifications (PTMs). These chemical alterations regulate receptor activity, intracellular signaling, and chromatin structure, shaping the neuroadaptations associated with SUD and relapse. This review emphasizes the central role of PTMs in modulating protein stability and function, contributing to drug-induced changes in key brain regions such as the nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus (HPC). Additionally, the therapeutic potential of targeting PTMs and their regulatory enzymes is discussed as a promising avenue for developing more precise, effective treatments for SUD. We explore how PTMs influence synaptic remodeling, gene expression, and behavior. Finally, we highlight emerging proteomic techniques for identifying PTM-related biomarkers and molecular signatures that may aid in understanding disease progression.