Sirtuins refer to a family of histone deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) (Wu et al., 2022) and contain seven members in mammals (Zhang et al., 2020; Zhao et al., 2022). As a member of the sirtuins family, sirtuin3 (SIRT3) is mainly localized in the mitochondrial matrix and inner membrane under normal physiological states (Mishra et al., 2023; Yang, Zhou, Liu, Chen, & Wang, 2023; Zhang et al., 2023), and its activity can regulate mitochondrial function (Naia et al., 2021). Under mitochondrial stress, such as a decrease in matrix pH and the loss of mitochondrial membrane potential, SIRT3 dissociates from the inner membrane (Yang et al., 2016) and deacetylates a large number of target proteins. Examples of these proteins include isocitrate dehydrogenase 2 (IDH2) (Ma et al., 2021), pyruvate kinase M2 (Zhao et al., 2022), β-catenin (Chen et al., 2022), and forkhead box O3a (FoxO3a) (Zhou et al., 2021). This process affects the mitochondrial electron transport chain (ETC) and ATP production (Mishra & Kaundal, 2023), which are closely related to energy metabolism, oxidative stress, inflammation, and apoptosis (Cortés-Rojo, Vargas-Vargas, Olmos-Orizaba, Rodríguez-Orozco, & Calderón-Cortés, 2020; Gong et al., 2021; Zhang, Liu, et al., 2023). Of note, whole-organism SIRT3 deficiency manifests as metabolic alterations, especially in liver, which is an essential metabolic organ (Dittenhafer-Reed et al., 2015; Qian et al., 2021). Due to these factors, the regulatory role of SIRT3 in the liver should not be ignored.

Liver fibrosis, resulting from chronic liver diseases, such as viral hepatitis, non-alcoholic fatty liver disease (NAFLD), drug-induced injury, and alcoholic fatty liver disease (ALD), is a reversible wound-healing response to liver injury characterized by the accumulation of extracellular matrix (ECM) (Luangmonkong, Parichatikanond, & Olinga, 2023; Zong et al., 2021). Recently, studies have shown that the development of liver fibrosis are closely related to hepatocyte damage, the recruitment of inflammatory cells, the activation of hepatic stellate cells (HSCs), and the role of liver sinusoidal endothelial cells (LSECs) (Cai et al., 2020). Specifically, SIRT3 protects hepatocytes from oxidative stress by enhancing reactive oxygen species (ROS), scavenging, and maintaining mitochondrial integrity (Liu et al., 2017). Similarly, SIRT3 attenuates the inflammatory infiltration of macrophages and reduces the expression of inflammatory factors by inhibiting the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome (Zhang Tian et al., 2020). Furthermore, SIRT3 inhibits the activation of HSCs by mediating the downstream signaling pathway of transforming growth factor-β (TGF-β)-Smad in liver fibrosis (Zhou, Wang, Li, Wang, & Lin, 2018). Taken together, SIRT3 plays a key role in the development of liver disease and is expected to be a potential target for the prevention and treatment of liver fibrosis.

This review summarizes the pharmacological effects of SIRT3 in detail based on recent research, particularly those focusing on the liver. We will also discuss the roles of drugs that regulate SIRT3, thereby contributing to liver fibrosis prevention and therapy.