Protection by Vitis vinifera L. Against Cisplatin-Induced Testicular Injury: Oxidative Stress, Inflammation, and Ferroptosis

<b>Background/Objectives</b>: Testicular toxicity is one of the most important chemotherapeutic adverse effects of Cisplatin (Cisp), which restricts its use and effectiveness. This study investigated the preventive effects of <i>Vitis vinifera</i> L. extract on Cisp-induced testicular injury in rats. <b>Methods</b>: Forty adult albino male rats were allocated into four groups: control, <i>Vitis vinifera</i> L. extract, Cisp, and co-treated (<i>Vitis vinifera</i> L. extract + Cisp). Sperm motility and count, serum reproductive hormones, oxidative/antioxidant biomarkers, pro-inflammatory cytokines, ferroptosis biomarkers, and gene expression profiles were evaluated. <b>Results</b>: Cisp administration markedly impaired reproductive performance, as evidenced by significant declines in serum FSH, LH, testosterone, and sperm motility and count. Cisp also induced oxidative stress by elevating MDA, GSSG, GPx, and 8-OHdG, while reducing SOD, Catalase, NRF2, and Ho-1 along with total and reduced GSH levels. Moreover, it triggered strong inflammatory responses and ferroptosis activation, with notable up-regulation of NFκB, TNF-α, IL-1β, ferritin, and cathepsin. Gene expression analysis revealed down-regulation of ARNTL, PI3K, and miR-125b and up-regulation of ASCL4, GSK3B, and COX2 following Cisp exposure. Conversely, co-treatment with <i>Vitis vinifera</i> L. extract significantly ameliorated these alterations, restoring sperm quality, hormone balance, antioxidant defenses, and modulating inflammatory, ferroptosis, and genetic responses toward normalcy in addition to restoring testicular and epididymal histoarchitecture without any significant effect in NRF2 and ARNTL expression. Additionally, co-treated groups with <i>Vitis vinifera</i> L. extract showed a significant decline in NF-kB p65 and increased PCNA testicular immunoreactivity with a substantial down-regulation in NF-kB p65 and PCNA epididymal immunoreactivity. <i>Vitis vinifera</i> L. extract alone did not affect any studied parameters as compared to the control group. <b>Conclusions</b>: These findings suggested that <i>Vitis vinifera</i> L. extract has a significant protective effect against Cisp-related testicular injury through antioxidative, anti-inflammatory, and anti-ferroptotic mechanisms.