en Cellular and molecular Neuroscience Cellular and molecular Neuroscience Original Original <div style="text-align: justify;"><span style="font-size:14px;"><span style="font-family:Tahoma;"><span style="line-height:2;"><b>Introduction:</b> Mesenchymal stem cells (MSCs) possess robust regenerative and immunomodulatory properties, making them attractive candidates for cell-based therapies targeting tissue repair and immune modulation. However, their therapeutic efficacy is often limited by poor survival and vulnerability to oxidative stress. Maintenance of mitochondrial function and antioxidant defenses is therefore critical for preserving MSC viability and function in hostile microenvironments.<b><span style="font-family:&quot;Times New Roman&quot;,serif"></span></b><br> <b>Methods:</b> This study evaluated fluoxetine, a selective serotonin reuptake inhibitor with reported antioxidative effects, as an in vitro preconditioning agent in rat bone marrow-derived MSCs. Cells were treated with a non-cytotoxic concentration of fluoxetine, and the expression of key mitochondrial and antioxidant regulatory genes was assessed by quantitative real-time PCR. In addition, molecular docking was performed to predict potential interactions between fluoxetine and mitochondrial-related target proteins.<b><span style="font-family:&quot;Times New Roman&quot;,serif"></span></b><br> <b>Results:</b> Fluoxetine preconditioning preserved MSC viability and significantly increased the expression of nuclear factor erythroid 2&ndash;related factor 2 (NRF2), sirtuin 3 (SIRT3), and mitochondrial transcription factor A (TFAM), which are central regulators of antioxidant defense and mitochondrial quality control. In contrast, SIRT1 and PGC1&alpha; expression levels were not significantly altered. Docking analyses predicted favorable binding interactions between fluoxetine and several mitochondrial regulatory proteins, with the strongest predicted affinity observed for SIRT1, suggesting a potential protein-level mechanism independent of transcriptional regulation.<b><span style="font-family:&quot;Times New Roman&quot;,serif"></span></b><br> <b>Conclusion:</b> These findings indicate that fluoxetine preconditioning selectively modulates mitochondrial and antioxidant pathways in MSCs under basal conditions. Whether this transcriptional modulation translates into enhanced resistance to oxidative stress requires further functional validation. In addition, in vivo studies are required to determine the translational relevance of fluoxetine-preconditioned MSCs in regenerative medicine.&nbsp;</span></span></span></div> Fluoxetine, Mesenchymal stem cells (MSCs), Preconditioning, Mitochondrial, Oxidative stress, Regenerative medicine 0 0 http://bcn.iums.ac.ir/browse.php?a_code=A-10-8536-1&slc_lang=en&sid=1 Shahrzad Nazari 13700319475328460058424 13700319475328460058424 No Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran Elahe Motevaseli 13700319475328460058425 13700319475328460058425 No Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran Maryam Farahmandfar 13700319475328460058426 13700319475328460058426 No Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran Ashraf Moini 13700319475328460058427 13700319475328460058427 No Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. Gholamreza Hassanzadeh 13700319475328460058428 13700319475328460058428 No Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran