<p>T-cell lymphoma (TCL) is a prevalent malignancy characterized by the aberrant proliferation of T cells. The molecular mechanism underlying TCL remains poorly understood, and effective therapeutic strategies are still limited. Maprotiline, a highly selective norepinephrine reuptake blocker, is primarily used in the treatment of various types of depression. Intriguingly, its potential therapeutic utility and underlying mechanisms in TCL have not been previously explored. In this study, we demonstrated for the first time that maprotiline significantly inhibits proliferation and migration while promoting apoptosis in TCL cells. Furthermore, in vivo experiments using TCL xenograft mouse models revealed that maprotiline treatment effectively suppresses tumor progression while maintaining a favorable safety profile with minimal toxicity. Mechanistically, our findings reveal that maprotiline exerts its anti-tumor effect by regulating the AKT/mTOR signaling pathway in TCL. Notably, we discovered that maprotiline substantially enhances the sensitivity of TCL cells to histone deacetylase inhibitor, thereby unveiling a promising combination therapeutic strategy for TCL treatment. These findings not only expand our understanding of maprotiline’s pharmacological potential beyond its conventional antidepressant use, but also provide a novel therapeutic avenue for addressing the clinical challenges in TCL management.</p>