Sirtuin 3 (SIRT3) (SIRT3)

Sirtuin 3 (SIRT3) is a primary mitochondrial NAD+-dependent protein deacetylase that plays a critical role in maintaining mitochondrial homeostasis and regulating cellular metabolism [10, 15]. It functions as a key modulator of the ferroptosis pathway by controlling reactive oxygen species (ROS) production and lipid peroxidation through the deacetylation of various mitochondrial substrates, such as superoxide dismutase 2 (SOD2) and isocitrate dehydrogenase 2 (IDH2) [1, 2, 4]. In the context of ferroptosis, SIRT3 activity generally exerts a protective effect by reducing oxidative stress and maintaining the integrity of the glutathione (GSH)/GPX4 antioxidant system [11, 14]. However, its role can be context-dependent, particularly in cancer, where it may act as either a tumor suppressor or an oncogene depending on the metabolic state of the cell [10, 17]. SIRT3 is considered a promising therapeutic target for a wide range of conditions, including cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes, where its activation can mitigate tissue damage [1, 15, 18]. Conversely, in specific oncogenic settings like glioblastoma, SIRT3 inhibition may be leveraged to sensitize tumor cells to ferroptotic cell death [5]. Small molecule modulators, such as the activator honokiol and the inhibitor 3-TYP, are currently being explored to harness SIRT3's regulatory potential in clinical applications [10, 13]. Research into the SIRT3-related ferroptosis pathway continues to uncover novel mechanisms of cell death regulation that could lead to innovative treatments for age-related and inflammatory diseases [4, 7].

Other names

NAD-dependent protein deacetylase sirtuin-3, mitochondrialSIR3Sirtuin-3Mitochondrial sirtuin 3

SIRT3 acts as an NAD+-dependent deacetylase that targets mitochondrial proteins such as SOD2, IDH2, and p53 [1, 2, 10]. By deacetylating and activating SOD2 and IDH2, SIRT3 enhances the cell's antioxidant capacity, reducing ROS levels and lipid peroxidation, which are the primary drivers of ferroptosis [4, 14]. In some contexts, SIRT3 also regulates ferroptosis by modulating the p53/SLC7A11 axis or the AMPK/mTOR pathway [2, 3, 11].