International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 244-252 http://medscipublisher.com/index.php/ijccr 244 Review and Progress Open Access Therapeutic Targeting of the SIRT3-FOXO3a-SOD2 Network in Sepsis: Current Evidence and Future Prospects Tiantian Li, Jie Zhang Institute of Life Science, Jiyang College of Zhejiang A&F University, Zhuji, 311800, Zhejiang, China Corresponding author: jie.zhang@jicat.org International Journal of Clinical Case Reports 2025, Vol.15, No.5 doi: 10.5376/ijccr.2025.15.0025 Received: 10 Aug., 2025 Accepted: 14 Sep., 2025 Published: 30 Oct., 2025 Copyright © 2025 Li and Zhang, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Li T.T., and Zhang J., 2025, Therapeutic targeting of the SIRT3-FOXO3a-SOD2 network in sepsis: current evidence and future prospects, International Journal of Molecular Medical Science, 15(5): 244-252 (doi: 10.5376/ijccr.2025.15.0025) Abstract This study explored the severe inflammation, oxidative stress and problems of many organs in sepsis. Mitochondrial damage is the key to its development. The SIRT3-FOXO3a-SOD2 signaling network is an important component for maintaining mitochondrial integrity and cellular antioxidant capacity. SIRT3 is a mitochondrial deacetylase. It can enhance the activity of the transcription factor FOXO3a and the antioxidant enzyme SOD2, thereby reducing the accumulation of reactive oxygen species (ROS). When sepsis occurs, this axis does not work well, leading to oxidative damage and cell death. Early studies (before human trials) have shown that using drugs or genetic alterations to repair this pathway can reduce organ damage, prevent pyroptosis, and help more people survive. Although animal experiments are progressing smoothly, the use of this method in real patient care remains uncommon. This study also verified the role of the SIRT3-FOXO3a-SOD2 axis in sepsis. It focuses on the treatment methods targeting this approach and discusses the future steps for manufacturing biomarkers and conducting clinical trials. This mitochondrial signaling network provides a new and scientifically based approach for treating organ failure caused by sepsis. Keywords Sepsis; SIRT3; FOXO3a; SOD2; Oxidative stress 1 Introduction Sepsis is a major global health issue that causes high morbidity and mortality rates among people of all ages. The World Health Organization and recent epidemiological studies have pointed out that there are several million cases of sepsis each year, among which the mortality rate of severe patients is more than 20% to 40% (Xu et al., 2016). The diversity of sepsis, the rapid development of organ failure, and the lack of targeted treatment methods other than supportive treatment all affect the treatment outcome. The currently adopted intervention methods are mainly to control infection and support organ function, but these methods often fail to address the underlying cellular and molecular abnormalities that lead to adverse consequences (Xu et al., 2020). One obvious feature in the pathogenesis of sepsis is the problem of mitochondrial function, which affects energy production, generates a large amount of reactive oxygen species (ROS), and also causes oxidative damage to cellular components. Abnormal mitochondrial function not only leads to organ failure but also perpetuates the processes of inflammation and apoptosis. The SIRT3-FoxO3a-SOD2 network has been confirmed to be an important regulatory factor for mitochondrial integrity and antioxidant defense. sirt3 promotes the deacetylation of SOD2, thereby enhancing its ability to clear ros, while FOXO3a is responsible for coordinating the expression of antioxidant genes (Xu et al., 2016; Xu et al., 2020). The dysfunction of this axis will aggravate the oxidative stress and tissue damage caused by sepsis. This study will explore the key roles of mitochondrial dysfunction and oxidative stress in sepsis. The SIRT3-FOXO3a-SOD2 network is a very promising therapeutic target. In sepsis models, activating SIRT3 with drugs or adjusting its downstream active substances can reduce organ damage and increase survival rates. This study will also analyze the existing evidence supporting this treatment method, with a focus on explaining its basic mechanisms and principles. At the same time, identify the deficiencies of these research results in clinical application as well as their future development directions. Deepening the understanding of this method may lay the foundation for the development of new treatment approaches that can address the root causes of organ dysfunction resulting from sepsis.
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