International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 244-252 http://medscipublisher.com/index.php/ijccr 249 acetylation of FOXO3a, making oxidative stress more severe. If SIRT3 levels are restored early, the acetylation of FOXO3a can be reduced and pyroptosis can also be alleviated. This indicates the critical time for treatment (Wu et al., 2023). Figure 2 Potential therapeutic targets in sepsis intervention (Adopted from Zhang et al., 2023) Image caption: Concerning the signaling pathways aimed at, the proposed therapeutic target for sepsis primarily encompasses the following pathway categories: (1) targeting DAMPs (including host cell stress), SESN2, and Park 7; (2) targeting inflammatory mediators (anti-inflammatory), JAK–STAT, HMGB1, GSDMD, and SQSTM1; (3) immune checkpoint modulation, PD-1/PD-L1; (4) restoration of complement and anticoagulant properties, C3a/C5a; (5) endothelial barrier stabilization, Ang/Tie2; (6) targeting the endoplasmic reticulum, STING; The discovery of therapeutic targets is a promising new strategy that has a wide range of therapeutic effects in experimental studies of sepsis (Adopted from Zhang et al., 2023) However, in intestinal tissues, the changes are different. The damage caused by sepsis is associated with stronger Cx43 and ROS signaling, which in turn activates the JNK1/Sirt1/FOXO3a pathway. These changes occurred at different times. This indicates that the same signaling pathways may vary with time and different organs (Zou et al., 2019). Understanding these changing patterns in specific cases is crucial for formulating effective and targeted treatment methods. 6.2 Lack of information on human trials and transformation Even though results from animal tests are promising, not much progress has been made in using the SIRT3-FOXO3a-SOD2 pathway to treat people. Most of the current evidence comes from mouse sepsis models made by cecal ligation and puncture (CLP) or lipopolysaccharide. These can't fully show how different human sepsis can be. Even though resveratrol and other enhancers have been shown in animal studies to bring back SIRT1/3 activity and reduce organ damage (Xu et al., 2016), these methods haven't been checked through strict human trials (Xuan, 2024). In addition, there is a gap in information regarding the absorption, distribution, metabolism, excretion of SIRT3 compounds in patients with sepsis, as well as their safety. In the absence of human data, it is difficult to determine whether those treatment methods that regulate the acetylation of FOXO3a or enhance the function of SOD2 are safe and effective in practical applications. More translational research is needed to narrow the gap between laboratory findings and clinical applications (You et al., 2024).
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