Certain SSRIs boost Lp(a) uptake into cells via serotonin and a plasminogen receptor, raising the prospect of repurposing them as Lp(a)-lowering drugs (J Lipid Res 2025)

We recently found that plasminogen receptors regulate the plasma membrane binding and uptake of Lp(a) via macropinocytosis. In this study, we sought to further define lipoprotein(a) [Lp(a)] macropinocytosis, discovering an unexpected role for antidepressants and serotonin in the regulation of this process. We found that the tricyclic antidepressant imipramine enhanced Lp(a) uptake, in contradiction of its published role as a macropinocytosis inhibitor. Extending these experiments to the commonly used serotonin uptake inhibitors (SSRIs) citalopram, sertraline, fluoxetine, and paroxetine, we found that citalopram and paroxetine stimulated Lp(a) uptake. Imipramine and citalopram enhanced cell surface binding of Lp(a) to increase uptake by macropinocytosis. Consistent with imipramine and citalopram boosting extracellular serotonin levels, serotonin itself also enhanced Lp(a) surface binding and uptake. In contrast to Lp(a), imipramine and citalopram had no effect on low-density lipoprotein (LDL) uptake. Imipramine and serotonin increased expression of the plasminogen receptor with a C-terminal lysine (PlgRKT), a receptor known to enhance cell surface binding of Lp(a), likely accounting for their effects on Lp(a) uptake. Finally, imipramine and citalopram increased Lp(a) delivery into Rab11 recycling endosomes but not degradative pathways in the cell. These findings indicate SSRIs such as citalopram and paroxetine may have utility as a potential Lp(a)-lowering therapeutic in people suffering from depression who often have elevated Lp(a) levels and an increased risk of cardiovascular disease.