Nicotinamide Riboside Attenuates Cisplatin-Induced Hepatorenal Toxicity Through Restoration of NAD+ Homeostasis and Nrf2/NQO1-Dependent Antioxidant Signaling
TL;DR
Nicotinamide riboside exerts protective effects against cisplatin-induced hepatorenal toxicity that are mechanistically linked to activation of the Nrf2/NQO1 antioxidant pathway and restoration of hepatic NAD+ homeostasis.
Abstract
Background: Cisplatin is a widely used chemotherapeutic agent whose clinical application is often limited by severe hepatorenal toxicity associated with oxidative stress and cellular injury. Nicotinamide riboside (NR), a natural precursor of nicotinamide adenine dinucleotide (NAD+), has emerged as a promising cytoprotective compound with antioxidant and metabolic regulatory properties. This study investigated the protective effects of NR against cisplatin-induced hepatorenal toxicity and explored its potential mechanisms of action. Methods: Thirty-six adult male Wistar rats were randomly assigned to four groups (n = 6): control, cisplatin (7 mg/kg, i.p.), nicotinamide riboside (50 mg/kg/day, orally), and cisplatin plus NR. Renal and hepatic function biomarkers, lipid profile parameters, oxidative stress markers, and antioxidant status were evaluated. Relative mRNA expression of Nrf2 and NQO1 was determined using RT-qPCR. Histopathological examinations of liver and kidney tissues were also performed. Results: Cisplatin administration induced marked hepatorenal injury, evidenced by significant elevations in serum KIM-1 (395.27 vs. 116.04 ng/mL), urea (71.16 vs. 21.33 mg/dL), creatinine (3.49 vs. 0.26 mg/dL), AST (325.83 vs. 95.16 U/L), and ALT (102.83 vs. 45.50 U/L), accompanied by dyslipidemia, oxidative stress, and severe histopathological alterations. NR treatment significantly attenuated these changes, reducing KIM-1, urea, creatinine, AST, and ALT by 55.5%, 47.8%, 48.1%, 55.4%, and 33.5%, respectively, compared with the cisplatin group. NR also improved antioxidant status by increasing GSH and SOD levels while reducing MDA and NO concentrations. Hepatic NAD+ levels and the NAD+/NADH ratio were significantly decreased by cisplatin and significantly restored by NR treatment. In addition, NR significantly upregulated the relative mRNA expression of Nrf2 and NQO1 and markedly preserved hepatic and renal histological architecture. Pharmacological inhibition of Nrf2 with ML385 significantly attenuated these protective effects of NR across biochemical, lipid, and oxidative stress parameters, confirming that they are, at least in part, Nrf2-dependent. Conclusions: Nicotinamide riboside exerts protective effects against cisplatin-induced hepatorenal toxicity that are mechanistically linked to activation of the Nrf2/NQO1 antioxidant pathway and restoration of hepatic NAD+ homeostasis. This finding supports the potential of NR as an adjunctive strategy for mitigating cisplatin-associated hepatorenal injury and warrants further preclinical and clinical investigation.