SLC6 transporters as pharmacological targets in depression: Molecular mechanisms and therapeutic strategies.

Depression is one of the leading causes of disability globally. Maintaining neurotransmitter homeostasis is essential not only for the prevention but also for the effective treatment of psychiatric disorders, particularly depression. Solute carrier 6 (SLC6) transporters, as key membrane proteins associated with the neurotransmitter reuptake pathways at the presynaptic membrane of the central nervous system, mediate neurotransmitter reuptake through Na+ and Cl- dependent co-transport. These transporters are crucial in regulating a wide range of physiological processes and have been closely linked to the pathophysiology of depression, positioning them as central targets for a variety of antidepressant drugs. SLC6 transporter inhibitors exert antidepressant effects through multiple mechanisms, including increasing synaptic cleft neurotransmitter concentrations, inhibiting neuroinflammation, and suppressing the overactivation of the hypothalamic-pituitary-adrenal (HPA) axis, while also regulating signaling pathways and enzyme activities. As a result, these inhibitors have become a prominent strategy in the development of antidepressant treatments. Among them, the development of new multi-target inhibitors and natural products has introduced novel drug candidates for depression, expanding the therapeutic arsenal. This review systematically summarizes the basic characteristics, structural differences, molecular mechanisms of SLC6 transporters, and the latest research progress on their inhibitors. It also highlights the clinical application potential of these inhibitors and their widespread side effects, offering insights for the treatment of depression targeting SLC6 transporters.