Vortioxetine mitigates methotrexate-induced oral mucosa injury via sirtuin 1 pathway and intrinsic apoptosis signaling

Background Methotrexate (MTX) commonly causes oral mucositis by inducing epithelial cytotoxicity and inflammation, leading to functional impairment and treatment limitations. Therefore, agents that can protect oral tissues without reducing MTX efficacy are needed. Vortioxetine (VOR), with its reported anti-inflammatory and antioxidant actions, may offer such therapeutic potential. Methods Thirty-two adults female Wistar rats were divided into four groups: Control, MTX, VOR and MTX + VOR (n = 8 each). VOR (10 mg/kg/day, intraperitoneally [i.p.]) was administered continuously for five days and a single dose of MTX (20 mg/kg, i.p.) was injected 30 minutes after the first VOR dose on day 1. Maxillary gingiva and tongue tissues were harvested on day 5 for histopathological, immunohistochemical (caspase-3 [CAS-3], tumor necrosis factor [TNF-α]) and molecular (sirtuin 1 [SIRT1], nuclear factor erythroid 2-related factor 2 [NRF2], peroxisome proliferator-activated receptor gamma coactivator 1-alpha [PGC1α], B-cell lymphoma 2 [BCL2], and BCL2-associated X protein [BAX]) analyses. Results MTX treatment caused increased TNF-α and CAS-3 immunoexpressing, leading to severe epithelial degeneration, hyperemia and inflammatory cell infiltration in the oral mucosa. Gene expression analysis supported that there was a significant upregulation of proapoptotic (BAX, CAS-3) and inflammatory markers (TNF-α) whereas a downregulation of mitochondrial regulators (SIRT1, NRF2, PGC1α, BCL2). Co-treatment with VOR markedly reversed these changes. Conclusion VOR significantly ameliorated the damage caused by MTX to the oral mucosa by interfering with the SIRT1/NRF2/PGC1α antioxidant axis and suppressing the BAX/BCL2/CAS-3 apoptotic pathway. These results indicate that VOR can be used as a valuable therapeutic agent that can be combined with chemotherapy to alleviate side effects in the oral mucosa by restoring redox homeostasis, mitochondrial integrity and cellular survival signals.