{"paper_id":"9769cfc3-6acf-4d0f-92f1-5b57b29f52be","body_text":"Abstract\nAims\nMethotrexate (MTX), a commonly used chemotherapeutic and immunosuppressive agent, is known to induce significant ovarian toxicity through mechanisms involving oxidative stress, inflammation, and apoptosis. Vortioxetine (VTX), a novel antidepressant with proven neuroprotective and anti-inflammatory properties, has not yet been evaluated in the context of chemotherapy-induced gonadotoxicity. This study aimed to investigate the protective effects of VTX against MTX-induced ovarian injury in a rat model by employing comprehensive histopathological and immunohistochemical evaluations.\nMethods and Results\nThirty-two adult female Wistar Albino rats (300–350 g) were randomly divided into four equal groups (n = 8): Control, MTX, MTX + VTX, and VTX. Ovarian damage was induced with a single intraperitoneal injection of MTX (20 mg/kg), while VTX was administered daily (10 mg/kg) by oral gavage for five days. Rats were sacrificed on day 5, and bilateral ovaries were collected. Histopathological evaluation included follicular degeneration, vascular congestion, hemorrhage, and inflammatory cell infiltration. Immunohistochemical analyses were performed for 8-Hydroxy-2'-deoxyguanosine (8-OHdG), nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), caspase 3 (Cas-3), and Anti-Müllerian hormone (AMH) to assess oxidative stress, inflammation, apoptosis, and ovarian reserve. MTX administration caused severe follicular atresia, hemorrhage, and dense neutrophil infiltration. Immunohistochemically, 8-OHdG, NF-κB, TNF-α, and Cas-3 expressions were significantly elevated, while AMH was markedly reduced. VTX co-treatment significantly attenuated histological damage and modulated the expression of all biomarkers, indicating potent protective effects. VTX alone did not induce deleterious changes.\nConclusion\nVTX exhibits a robust protective effect against MTX-induced ovarian injury via suppression of oxidative stress, inflammatory response and apoptotic pathways, while simultaneously preserving ovarian reserve. These findings highlight a novel application for VTX in fertility preservation strategies during chemotherapeutic interventions.\nSimilar content being viewed by others\nData Availability\nThe datasets generated and/or analyzed in this study are available from the corresponding author upon reasonable request. We have not used any AI tools or technologies to prepare this manuscript.\nReferences\nAguilera-Aguirre L, Bacsi A, Radak Z, Hazra TK, Mitra S, Sur S, Brasier AR, Ba X, Boldogh I (2014) Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-κB pathway. 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E.S. and I.N. performed the experimental procedures and histological evaluations. E.S. and I.N. carried out the immunohistochemical analysis and statistical evaluation. H.A. and E.S. wrote the initial draft of the manuscript. H.A. and O.K. prepared the figures and tables. All authors reviewed and approved the final version of the manuscript.\nCorresponding author\nEthics declarations\nConflicts of Interest\nThe datasets generated and/or analyzed in this study are available from the corresponding author upon reasonable request. We have not used any AI tools or technologies to prepare this manuscript. Sarman E. and the co-authors have no conflicts of interest to declare in association with this study. The authors have no potential conflicts of interest to disclose.\nAdditional information\nPublisher's Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nSupplementary Information\nBelow is the link to the electronic supplementary material.\nRights and permissions\nSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.\nAbout this article\nCite this article\nSarman, E., Asci, H., Ozcan, K.N. et al. Vortioxetine protects against methotrexate-induced ovarian toxicity through anti-inflammatory, antioxidant and antiapoptotic pathways: a multi-marker immunohistochemical study. J Mol Histol 56, 356 (2025). https://doi.org/10.1007/s10735-025-10642-w\nReceived:\nAccepted:\nPublished:\nVersion of record:\nDOI: https://doi.org/10.1007/s10735-025-10642-w","source_license":"CC0","license_restricted":false}