International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 244-252 http://medscipublisher.com/index.php/ijccr 248 Researchers are also exploring methods of gene therapy, such as using better vectors or microbubble delivery systems to deliver SIRT3 or SOD2 genes to where they are needed. These methods have worked in large animal models of cardiac injury. The focus of these attempts is to continuously enhance SOD2 and other antioxidant defense capabilities, providing a possible long-term approach to prevent organ problems caused by sepsis (Qin et al., 2023). More research is needed to improve the administration methods and to check whether they are safe and effective in the human body. 5 Preclinical Evidence and Therapeutic Potential 5.1 The efficacy of targeted networks in animal models of sepsis Preclinical studies have shown that activating the SIRT3-FOXO3a-SOD2 network with drugs can significantly improve the disease progression in animal models of sepsis. For instance, in rats with sepsis, after treatment with resveratrol, the activity of SIRT3 was restored, the level of acetylated SOD2 decreased, oxidative stress improved, mitochondrial function was enhanced, and survival time was prolonged. This is reflected in sepsis-related acute kidney injury. The potential of taking this approach as the therapeutic target (Xu et al., 2016). Similarly, in mouse models of sepsis-induced myocardial dysfunction, insufficient SIRT3 makes cardiac function worse. However, activating SIRT3 with emodin can alleviate myocardial dysfunction and improve cardiac function, but this effect only occurs when SIRT3 functions normally (Xu et al., 2020). These findings suggest that SIRT3 plays a core role in preventing organ dysfunction during sepsis. 5.2 Potential of combined and multi-target therapy Targeting multiple parts of the SIRT3-FOXO3A-SOD2 network or combining the activation of SIRT3 with other therapeutic approaches may yield better results in the treatment of sepsis. The mutual influence among SIRT3, FOXO3a and SOD2 indicates that, compared with regulating only a single molecule, simultaneously regulating these factors can more effectively restore mitochondrial function and reduce oxidative damage (Xu et al., 2016; Xu et al., 2020). Furthermore, the combination of SIRT3 enhancers with other drugs that can affect important pathways in the course of sepsis (such as inflammation or immune imbalance) may enhance the therapeutic effect and address multiple pathogenic factors of sepsis (Figure 2) (Zhang et al., 2023). The complex interweaving of different signaling pathways in sepsis suggests that this treatment approach targeting multiple sites simultaneously is worth trying. 5.3 Evaluate the treatment window, dosage and safety issues Preclinical studies have shown that when using drugs that regulate the SIRT3-FOXO3a-SOD2 network, the duration and dosage of administration are the keys to achieving the best therapeutic effect. For instance, the therapeutic effects of resveratrol and emodin were observed through specific medication regimens and depended on whether SIRT3 could function normally. This indicates that the time range of treatment and the appropriate patient population need to be carefully determined (Xu et al., 2016; Xu et al., 2020). Safety issues also need to be taken into account, as excessive activation of this network or the drug acting on other unrelated areas may disrupt the stable state of the cells. Although current animal studies have shown the benefits of treatment and no serious adverse consequences have been found, further research is needed to determine safe and effective medication methods and to evaluate the safety of long-term use in preclinical applications (Xu et al., 2016; Xu et al., 2020). 6 The Difficult Problems Faced and the Unsolved Scientific Questions 6.1 Time and Organ differences in network regulation One of the key questions that is not well understood is how the SIRT3-FOXO3a-SOD2 signaling pathway is controlled at different times and in different organs during the exacerbation of sepsis. Research shows that the quantity of SIRT3 and its control over FOXO3a and SOD2 vary with the stage and severity of sepsis. For instance, in lung injury caused by sepsis, the level of SIRT3 will decline during the acute phase. This will lead to excessive
RkJQdWJsaXNoZXIy MjQ4ODYzNA==