NAD + in fatty liver disease: mechanistic insights and associated targets

Fatty liver disease, encompassing metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD), is frequently linked to high-calorie diets, excessive alcohol consumption, or other metabolic disorders. These conditions can escalate to cirrhosis and even hepatocellular cancer (HCC), resulting in a substantial economic burden worldwide. Nicotinamide adenine dinucleotide (NAD +) is a coenzyme that plays a critical role in cellular metabolism and homeostasis. Its depletion has been observed in cases of fatty liver disease, while restoration of NAD + levels has been shown to mitigate the initiation and progression of disease. This review presents advances of NAD + in the pathophysiology of fatty liver disease, focusing on the biological roles of NAD + in liver lipid accumulation, oxidative stress, endoplasmic reticulum stress (ERS), inflammation, autophagy, and liver fibrosis during the development of fatty liver disease. Furthermore, the potential of NAD + as a therapeutic target for fatty liver disease is also discussed.