Morin Mitigates 5-Fluorouracil-Induced Nephrotoxicity by Activating Nrf2/HO-1 and FXR, and Suppressing ERK/VCAM-1 and NF-κB Pathways.

5-Fluorouracil (5-FU) is a DNA analog used in chemotherapy to treat various tumors. However, the clinical use of 5-FU is limited due to its severe adverse effects, particularly its nephrotoxicity. Morin (MRN) is a flavanol found in many different plants, including those in the Moraceae family, and has anti-inflammatory and antioxidant bioactivities. The protective effects of MRN against experimental 5-FU-induced kidney injury were investigated in this work. The rats were assigned to four groups in our study: control, MRN (50 mg/kg), 5-FU (30 mg/kg), and 5-FU + MRN. The administration of MRN caused a significant (P < 0.05) decrease in the serum urea and creatinine levels and a reduction in the histopathological changes induced by 5-FU, as shown by H&E, PAS, and Sirius red staining. IHC shows that MRN attenuates renal oxidative stress induced by 5-FU via co-activation of Nrf2, HO-1, and FXR. MRN protects against renal inflammation induced by 5-FU, as evidenced by decreased TNF-α and IL-6 levels in the rat kidney mediated by the downregulation of the ERK1/2 and VCAM-1 proteins and decreased NF-κB phosphorylation as shown by Western blotting. These findings support using MRN as a novel and promising treatment for 5-FU-induced nephrotoxicity.