TY  - JOUR
AU  - Wang, Jinyang
AU  - Wang, Jianan
AU  - Xie, Wei
AU  - Shen, Qi
AU  - Wang, Chengbin
AU  - Li, Ruibing
AU  - Deng, Shixiong
PY  - 2026
TI  - The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy
JO  - Genes & Diseases
SN  - 2352-4820
VL  - 13
IS  - 5
AB  - Excessive alcohol consumption leads to neurodegeneration, driven primarily by oxidative stress and mitochondrial dysfunction, yet no specific treatment exists. Nicotinamide riboside chloride (NRC), a nicotinamide adenine dinucleotide precursor, has demonstrated therapeutic potential in mitigating mitochondrial dysfunction in heart failure, but its role in alcohol-induced neurodegeneration remains unexplored. This study investigated NRC’s neuroprotective effects using behavioral tests, serum ethanol and inflammatory marker analysis, hematoxylin-eosin staining, and molecular assays of in vitro models. Proteomics and GEO database analysis further elucidated the mechanisms of alcohol-induced brain injury. Results showed that NRC significantly improved alcohol-related cognitive impairment and neuroinflammation. Both our experimental data and external datasets identified mitochondrial dysfunction as a key driver of alcohol-induced neuronal damage, characterized by impaired mitophagy and disrupted mitochondrial unfolded protein response (UPRmt). NRC supplementation restored mitochondrial homeostasis by enhancing UPRmt and Fundc1-dependent mitophagy. Mechanistically, UPRmt inhibition abolished NRC’s protective effects by suppressing Fundc1 expression and mitophagy, whereas mitophagy inhibition did not affect UPRmt, suggesting a hierarchical regulation where UPRmt governs Fundc1-mediated mitophagy. In conclusion, alcohol disrupts mitochondrial quality control, but NRC counteracts neuronal toxicity by activating UPRmt and restoring Fundc1-driven mitophagy, offering a promising therapeutic strategy for alcohol-related neuronal damage.
UR  - https://doi.org/10.1016/j.gendis.2025.101886
DO  - 10.1016/j.gendis.2025.101886