Monoaminylation in Human Health and Disease: State of the Field, Challenges, and Emerging Directions.

Parallel to their roles in regulating receptor activation, mounting evidence suggests that monoamines are involved in protein post-translational modification, which regulates the physiological function of the nervous system and various pathophysiologically relevant conditions. These modifications, primarily including serotonylation, dopaminylation, and histaminylation, occur on both histone and non-histone proteins, thereby modulating gene transcription and protein function. This review comprehensively summarizes the types of monoaminylation, the catalytic enzymes and molecular mechanisms, and the corresponding monoamine transporters. Furthermore, we categorize and discuss the roles of monoaminylation across the human body in health and disease, highlighting their functional implications and therapeutic potential. We emphasize the need for precise methodologies to modulate monoamine levels in the context of pathological processes across various diseases. Finally, we outline persistent challenges in the field and suggest promising directions for future research, aiming to facilitate both mechanistic insight and translational applications.