Acylation Modifications at the Crossroads of Metabolism and Epigenetics: Unraveling the Neuroplasticity and Therapeutic Landscape of Depressive Disorders (Review)

Depressive disorders (DDs) are heterogeneous neuropsychiatric conditions arising from complex interactions among genetic susceptibility, environmental stress, metabolic disturbances, neuroinflammation and impaired neuroplasticity. Increasing evidence suggests that metabolic-epigenetic crosstalk contributes to DD pathophysiology. Protein acylation, which couples metabolite-derived acyl groups to histone and non-histone proteins, provides a potential molecular interface between cellular metabolism and the regulation of gene expression, protein function and intracellular signaling. The present review summarizes current evidence implicating major acylation modifications, including acetylation, crotonylation, succinylation, β-hydroxybutyrylation, lactylation, palmitoylation and myristoylation, in DDs. The current study discusses how dysregulated acylation may influence neuroplasticity and neuroimmune responses, and examines the roles of key regulatory enzymes in DDs. Furthermore, the present review summarizes that deacylases HDACs play a central, pivotal regulatory role in the pathological progression of DDs. Finally, it discusses emerging experimental and therapeutic strategies for DDs, including spatially resolved acyl-proteomics, single-cell analysis and targeted modulation of acylation-regulating enzymes. These approaches may clarify the cell-type- and brain-region-specific functions of acylation, and may facilitate the development of mechanism-based biomarkers and personalized therapeutic interventions for biologically defined subgroups of DDs. However, clinical translation remains challenging because causal evidence is still limited, acylation effects are highly cell- and context-specific, peripheral biomarkers may not reliably reflect brain alterations, and pharmacological targeting of acylation enzymes may be constrained by limited selectivity and off-target effects. Addressing these challenges may clarify the mechanistic significance of acylation in DDs and support the development of more precise biomarkers and mechanism-informed therapeutic strategies.