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Nicotinamide riboside alleviates doxorubicin-induced hepatotoxicity and nephrotoxicity by inhibiting ferroptosis

Yujie Ding^c,?, Qian Shi^a,b,?, Zhuowen Wen^a,b,?, Zhiyong Wang^a,b,?, Shining Xie^a,b, Weili Liu^a,b,*, Hongfei Xu^a,b,*

 
ABSTRACT:     Although doxorubicin (DOX) is often used to treat cancer, it causes iron-dependent and reactive oxygen species-related ferroptosis and has serious effects on off-target organs, leading to limited therapeutic use. New evidence suggests that nicotinamide riboside (NR), a micronutrient, may protect the liver and the kidney from injury. The precise mechanism, however, is still unknown. This research aimed to examine the potential protective benefits of NR against hepatotoxicity and nephrotoxicity induced by DOX. We created DOX-induced hepatotoxicity and nephrotoxicity models in C57 mice, demonstrating liver and kidney dysfunction, collagen accumulation with inflammation, oxidative stress, and apoptotic damage. The hepatorenal function and damage were evaluated by measuring serum levels of enzymes and biochemical parameters as well as tissue iron and histochemical tissue staining. Intriguingly, pretreatment with NR was associated with a decrease in serum alanine transaminase, aspartate aminotransferase, serum creatinine, and blood urea nitrogen levels. The reduction in histological damages including hemorrhages, localized necrosis, changes of ultrastructure in liver and kidney tissues, and collagen accumulation was observed. The DOX-induced changes in serum malondialdehyde, protein carbonyl, glutathione, glutathione peroxidases, tissue iron accumulation and iron content were all reversed by NR, demonstrating its antioxidative capabilities. Taken together, NR inhibits ferroptosis to exert its curative benefits against DOX-induced acute hepatorenal toxicity.

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* Corresponding author, E-mail: 405184703@qq.com, xuhongfei@suda.edu.cn

Received 23 Jun 2024, Accepted 0 0000