SUMOylation is a post‑translational modification whereby the SUMO peptide is covalently attached to lysine residues on target proteins influencing essential cellular processes. It plays pivotal roles in neurobiology and has been increasingly implicated in neurodegenerative diseases. In Huntington’s Disease (HD), for instance, SUMOylation contributes to the aggregation of mutant huntingtin (mHTT), and inhibition of this modification can mitigate disease-like traits and reduce mHTT aggregation, marking SUMO pathways as therapeutic targets. In our laboratory, we have shown that the SSRI antidepressant fluoxetine functions as a global SUMOylation inhibitor, both in vitro and in vivo. To investigate its effect on mHTT aggregation, we transfected HEK293T cells with SUMO1, SUMO2, and either HttQ25‑mCherry (non-pathogenic control) or HttQ74‑mCherry (pathogenic mHTT). Then cells were treated with either vehicle, fluoxetine (1 µM), or the specific SUMOylation inhibitor ML792 (0,02 µM). We employed immunofluorescence and confocal microscopy to visualize aggregate formation, alongside Western blot analysis to quantify global SUMOylation levels. Our results demonstrate that fluoxetine reduces the formation of mHTT aggregates, replicating the anti‑aggregation effects observed with ML792. Importantly, overexpressing either SUMO1 or SUMO2 abolishes fluoxetine’s protective effect, confirming that its anti‑aggregation activity is specifically mediated through the suppression of SUMOylation.