International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 244-252 http://medscipublisher.com/index.php/ijccr 245 2 The Molecular Basis of the SIRT3-FOXO3a-SOD2 Signaling Network 2.1 SIRT3: deacetylase activity and its role in mitochondrial regulation This study will explore that SIRT3 is a NAD+-dependent deacetylase existing in mitochondria, which plays a key role in maintaining mitochondrial stability and regulating cellular metabolism. SIRT3 can enhance mitochondrial function, promote ATP production and reduce mitochondrial stress by deacetylating key mitochondrial proteins, which is very important for cell survival under pathological conditions such as oxidative stress and inflammation (Gao et al., 2017). In various disease models, such as myocardial ischemia/reperfusion injury and intervertebral disc degeneration, enhancing the activity of SIRT3 has been proven to protect tissues by improving mitochondrial function and reducing oxidative damage (Chang et al., 2019; Ty et al., 2019). The protective effect of SIRT3 is closely related to its ability to activate downstream targets through deacetylation, especially FOXO3a and SOD2. When SIRT3 deacetylates these proteins, it can make them more stable and active, increase the content of antioxidant enzymes, and enhance the ability of cells to resist oxidative stress (Chang et al., 2019; Zhou et al., 2020). If SIRT3 decreases or disappears, it will lead to problems with mitochondrial function, more severe oxidative stress, and cells will be more vulnerable to tissue damage. This shows how important it is in regulating mitochondria and cellular defense mechanisms (Gao et al., 2017; Ty et al., 2019). 2.2 FOXO3a: activation mechanism, target genes and protective cellular functions FOXO3a is a transcription factor. It can control the expression of genes that help with antioxidant defense, cell death, and cellular stress response. Its activity is tightly managed through changes after translation, like acetylation and phosphorylation. SIRT3 removes acetylation from FOXO3a, making it more stable and helping it stay in the cell nucleus. This helps turn on the transcription of key antioxidant genes such as SOD2 and catalase (Sundaresan et al., 2009; Chang et al., 2019). This removal of acetylation also cuts down on the phosphorylation and ubiquitination of FOXO3a, which further stabilizes the protein and makes its protective effect stronger (Zhou et al., 2020). FOXO3a helps cells survive under pathological conditions by up-regulating antioxidant genes and reducing oxidative stress. In models of cardiac hypertrophy, neuropathic pain and nephrotoxicity, activation of the SIRT3-FOXO3a axis has been demonstrated to reduce ROS levels, inhibit apoptosis and maintain tissue function (Fu et al., 2017). When the activity of FOXO3a is disrupted due to increased acetylation or decreased expression, it leads to a decline in antioxidant defense capabilities, and cells become more sensitive to oxidative damage (Sundaresan et al., 2009). 2.3 SOD2: antioxidant defense function and upstream regulatory interaction SOD2 (superoxide dismutase 2) is a mitochondrial enzyme that can catalyze the conversion of superoxide free radicals into hydrogen peroxide and is the main defense substance of mitochondria against oxidative stress. Its expression and activity are jointly regulated by SIRT3 and FOXO3a. SIRT3 directly deacetylates SOD2 and enhances its enzymatic activity, thereby effectively eliminating ROS (Gao et al., 2017; Chang et al., 2019). Furthermore, FOXO3a promotes the transcription of the SOD2 gene and further increases its expression when cells are under stress (Sundaresan et al., 2009; Fu et al., 2017). SIRT3 and FOXO3a jointly control SOD2, which is crucial for maintaining mitochondrial REDOX balance and preventing oxidative damage. Test models show that if SIRT3 or FOXO3a is absent, SOD2 activity will decrease, superoxide in mitochondria will increase, and cell function will deteriorate (Chang et al., 2019). On the other hand, increasing SOD2 through the SIRT3-FOXO3a pathway can effectively protect cells from oxidative damage. This indicates that targeting this network might be a good approach for treating mitochondrial dysfunction and oxidative stress-related diseases (Sundaresan et al., 2009; Gao et al., 2017). 3 The Role of the 3-SIRT3-FOXO3A-SOD2 Network in the Pathophysiology of Sepsis 3.1 Changes in signal axis expression under sepsis conditions Sepsis is characterized by severe disruption of REDOX balance and mitochondrial function, which leads to abnormalities in protective signaling pathways. Among them, the SIRT3-FOXO3a-SOD2 axis was significantly
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