In conclusion, our study uncovered a causal link between regulated levels of ZDHHC21 expression, attenuated 5-HT1AR palmitoylation, and development of depressive symptoms making the restoration of 5-HT1AR palmitoylation (either by upregulation of ZDHHC21 or inhibition of miR-30a or -30e) a possible clinical strategy for the treatment of MDD. Here, ZDHHC21 is linked to major depressive disorder.