Citrus flavonoids mitigate the cisplatin-induced ovarian toxicity via dual modulation of Nrf2/HO-1 pathway and NF-κB axis

Abstract

Cisplatin (CIS) is an effective chemotherapeutic agent whose clinical use is limited by off-target toxicity, including damage to ovarian granulosa cells, characterized by oxidative stress and inflammation. Here, the cytoprotective potential of the citrus flavonoids, naringin (NG) and hesperidin (HP), was investigated in ovarian granulosa cells exposed to CIS-induced toxicity. Molecular docking demonstrated that NG and HP exhibited strong binding affinities for key antioxidant, nuclear factor erythroid 2–related factor 2 (Nrf2) and catalase (CAT) as well as anti-apoptotic B-cell lymphoma-2 (Bcl-2) proteins, while CIS preferentially interacted with pro-apoptotic targets. In vitro , CIS dose-dependently reduced cell viability and hormone secretion (progesterone and estradiol), and these reductions were significantly restored by co-treatment with NG or HP. CIS-induced oxidative injury, marked by elevated accumulation of reactive oxygen species (ROS), lipid peroxidation, and depletion of reduced glutathione (GSH), as well as key antioxidant defenses (superoxide dismutase (SOD) and catalase (CAT), was effectively mitigated by the NG and HP. Furthermore, NG and HP suppressed the CIS-triggered inflammation by inhibiting NF-κB activation and downregulating the release of major pro-inflammatory mediators (tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8, IL-1β). They also counteracted CIS-induced apoptosis by reducing phosphorylation of protein kinase B (Akt), cytochrome c (Cyt c) release, caspase (Cas) activation, and the Bcl-2-associated X protein ( Bax )/ Bcl-2 ratio. These findings demonstrated that NG and HP could protect ovarian granulosa cells from CIS-induced damage through dual regulation of the Nrf2/heme oxygenase-1 ( HO-1 ) antioxidant and nuclear factor kappa B ( NF-κB ) inflammatory axis, highlighting their potential as adjuvant therapies to mitigate chemotherapy-induced ovarian toxicity.