International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 244-252 http://medscipublisher.com/index.php/ijccr 247 3.3 Validation results from clinical samples and animal models Data from both patient samples and experimental animals can demonstrate the significance of the SIRT3-FOXO3a-SOD2 signaling network in the development of sepsis. In animal experiments, increasing the content of SIRT3 or using drugs to make it more active always plays a protective role. Wu et al. (2023) found that increasing the SIRT3 level in septic mice could significantly reduce the markers of oxidative stress and pyroptosis, while reducing SIRT3 would have the opposite effect. Furthermore, Zou et al. (2023) conducted a more detailed examination of the intestinal tissues of septic mice. They found that blocking upstream signaling molecules such as connexin43 would reduce the activity of downstream SIRT1 and FOXO3a, while also improving tissue conditions and reducing cell death. These results prove that this pathway is worthy of in-depth study and also indicate that its poor function is very common in organ damage related to sepsis. 4 Current Treatment Strategies for the Internet 4.1 Pharmacological activation of SIRT3 In sepsis and related diseases, enhancing the activity of SIRT3 with drugs has become a promising approach to restore normal mitochondrial function and reduce oxidative stress. Some substances, such as resveratrol and tannin, as well as newer drugs like ginsenoside Rh1 and sodium trans-butyrate (TSC), have been found to make SIRT3 more active. This improves the working state of mitochondria, reduces the generation of reactive oxygen species (ROS), and also prevents cell death. These drugs not only increase the quantity of SIRT3 protein, but also help its downstream targets (including FOXO3a and SOD2) undergo deacetylation and become active. This further enhances the antioxidant protection of the cells themselves (Chang et al., 2019; Gong et al., 2025). Animal experiments have shown that SIRT3 enhancers can significantly reduce organ damage and increase survival chances in oxidative stress and ischemia-reperfusion injury models, and the mechanism of action is similar to that of sepsis. For instance, TSC and ginsenoside Rh1 have been demonstrated to reduce the extent of myocardial infarction, improve cardiac function, and alleviate mitochondrial dysfunction by increasing the levels of SIRT3 and its downstream acting molecules (Chang et al., 2019; Gong et al., 2025). These results all support the possibility of using SIRT3 enhancers in the treatment of sepsis, but it still needs to be confirmed through human trials. 4.2 Methods for promoting the activation and entry of FOXO3a into the cell nucleus Another treatment approach is to promote the activation of FOXO3a and its entry into the cell nucleus, with the aim of enhancing the expression of genes related to antioxidant and cell protection. Sirt3-induced deacetylation of FOXO3a is a key step in stabilizing FOXO3a and facilitating its entry into the cell nucleus. This process can promote the expression of genes such as SOD2 and catalase (Chang et al., 2019). Some drugs that can enhance SIRT3, including ginsenoside Rh1, have been found to help FOXO3a enter the cell nucleus, reduce its acetylation level, and thereby improve its ability to control gene transcription (Gong et al., 2025). In addition, finding methods to prevent the phosphorylation or ubiquitination of FOXO3a can further stabilize this protein and prolong its protective effect. By enhancing the activity of FOXO3a, these methods help to reduce oxidative damage and programmed cell death in sepsis and related diseases (Chang et al., 2019; Gong et al., 2025). Therefore, in sepsis, simultaneously enhancing the activity of SIRT3 and FOXO3a is a synergistic approach to restoring REDOX balance and cellular resistance. 4.3 Attempts to enhance SOD2 through drug or genetic means Increasing the level or activity of mitochondrial antioxidant enzyme SOD2 is a strategy to directly eliminate excessive ROS and protect mitochondria from damage in sepsis. Drugs that can enhance the activity of SIRT3 or FOXO3a can indirectly increase the amount and activity of SOD2 by promoting its deacetylation and gene transcription. For instance, TSC and ginsenoside Rh1 have been proven to increase the quantity and activity of SOD2 protein, thereby reducing oxidative stress and improving the working state of mitochondria (Chang et al., 2019; Gong et al., 2025).
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