The protective effects of dapagliflozin on cisplatin-induced ovarian toxicity via NRF2-HO-1 pathway and TNF-?/Cas3 signaling

Abstract

This study aimed to investigate the immunohistochemical expression patterns of proliferating cell nuclear antigen (PCNA), heat shock protein-70 (HSP-70), and kisspeptin-1 (KISS-1), as well as the gene expression levels of nuclear factor erythroid 2–related factor 2 (NRF2), heme oxygenase-1 (HO-1), tumor necrosis factor-alpha (TNF-?), and caspase-3 (CAS-3) in cisplatin (CIS)-induced ovarian toxicity, and to evaluate the protective effects of dapagliflozin (DAPA). Thirty-two female Wistar albino rats (n = 8 per group) were divided into four groups: Control, CIS (7.5 mg/kg, intraperitoneal), CIS + DAPA (10 mg/kg DAPA, oral for 7 days + CIS), and DAPA alone. Ovarian tissues were harvested for immunohistochemical and genetic evaluations. PCNA, HSP-70, and KISS-1 immunoreactivities were semi-quantitatively scored, and the mRNA expression levels of NRF2, HO-1, TNF-?, and CAS-3 were assessed using real-time quantitative PCR. All results were statistically analyzed. CIS administration led to a marked increase in PCNA, HSP-70, and KISS-1 immunoexpression, along with downregulation of NRF2 and HO-1 and upregulation of TNF-? and CAS-3 gene expressions (p < 0.001 for all) compared to the control group, indicating enhanced cellular proliferation, oxidative stress, inflammation, and apoptosis. In the CIS + DAPA group, a significant attenuation in PCNA (p < 0.001), HSP-70 (p < 0.001), and KISS-1 (p < 0.001) expression levels, and a reversal of genetic alterations were observed compared to the CIS group, demonstrating that DAPA mitigated proliferative, stress-associated, inflammatory, and apoptotic changes induced by CIS expressions (p < 0.001 for all). Ovarian tissues in the DAPA-alone group maintained expression profiles similar to the control. DAPA exerts protective effects against CIS-induced ovarian damage by modulating proliferation, cellular stress, inflammation, and apoptotic pathways, as evidenced by the downregulation of PCNA, HSP-70, KISS-1, TNF-?, and CAS-3, and upregulation of NRF2 and HO-1. These findings suggest that DAPA may offer a novel therapeutic approach for preserving ovarian function in patients undergoing chemotherapy. © The Author(s) 2025.