Tert-butylhydroquinone attenuates anticancer drug paclitaxel-induced nephrotoxicity via inhibition of inflammation-mediated NF-κB/IL-6//TNF-α and modulation of oxidative stress-dependent Nrf2/caspase-3/GPX-4 signaling in rats

Paclitaxel (PTX) is an efficacious natural product-derived anticancer agent. It exerts a remarkable disruption of nanopore microtubule dynamics, thus inducing cytotoxic effects on cancer cells. However, its drawback is associated with non-targeted healthy organ damage, including nephrotoxicity. Therefore, we explored the mechanistic protective effect of tert-butylhydroquinone (TBHQ) against PTX-induced nephrotoxicity in male Wistar rats. For this purpose, rats were divided into four (n = 5) groups: normal control, TBHQ control (50 mg/kg body weight, administered from day 1 to day 14), PTX control (2 mg/kg body weight injected from day 1 to day 5) and TBHQ + PTX (with doses indicated above). PTX injection significantly impaired renal function leading to elevated serum urea, creatinine and uric acid levels and caused disruption of histological integrity. PTX markedly reduced the renal antioxidant enzyme mechanisms, Nrf2 and ferroptosis GPX-4 levels, whereas the levels of malondialdehyde MDA, caspase-3, and BAX were conspicuously elevated compared to the control. The renal NF-κB and cytokine (TNF-α, IL-1β and IL-6) expressions were significantly increased due to the PTX injection. TBHQ administration effectively reversed these alterations associated with oxidative inflammation, apoptosis and ferroptosis via restoring renal function, renal antioxidant enzyme activities and reducing MDA levels. TBHQ considerably improved renal Nrf2, GPX-4 and GSH followed by ameliorated histopathological changes. Taken together, our results suggest that TBHQ has protective effects against PTX-induced nephrotoxicity, and is a promising antioxidant agent with the potential to improve quality of life during PTX chemotherapy.