International Journal of Clinical Case Reports, 2025, Vol.15, No.5, 239-247 http://medscipublisher.com/index.php/ijmms 243 SIRT3 removes acetyl groups from FOXO3a. This helps FOXO3a bind to DNA and switch on antioxidant genes (Wu et al., 2022; Tyagi and Pugazhenthi, 2023). Chang et al. (2019) reported that mice lacking FOXO3a in heart cells showed reduced Catalase and SOD2, increased ROS, and greater heart injury. In the absence of SIRT3, FOXO3a remains in the cytoplasm and is inactive, even under stress (Tyagi and Pugazhenthi, 2023; Xian et al., 2025). When SIRT3 is present, it aids FOXO3a in moving into the nucleus to trigger more antioxidant enzymes (Wu et al., 2022). SIRT3 also directly targets these enzymes, removing acetyl groups from MnSOD at K68 to enhance superoxide clearance (Tyagi and Pugazhenthi, 2023). The natural compound Oroxylin A can boost SIRT3 activity, strengthening FOXO3a and MnSOD, lowering ROS, and protecting cells (Peng et al., 2024). In septic cardiomyopathy, when this axis fails, ROS builds up and damages the heart (Murugasamy et al., 2022). But if SIRT3 is activated, Catalase and SOD2 go up, MDA goes down, and heart function gets better (Xu et al., 2020). 4.2 Crosstalk with Nrf2, AMPK, and other signaling pathways The SIRT3-FOXO3a axis doesn’t work alone. It talks to other important stress-related systems like Nrf2 and AMPK (Zhao and Liu, 2021; Kim et al., 2022). Nrf2 is an important regulator of antioxidant genes, activating HO-1 and those involved in glutathione production (Hu et al., 2021). Kim et al. (2022) showed that Nrf2 can also boost Sirt3 expression, helping cells resist stress (Ning et al., 2024). SIRT3 and FOXO3a enhance Nrf2 activity, reducing ROS and supporting antioxidant enzymes like Catalase and SOD2 (Chang et al., 2019; Zhao and Liu, 2021). In sepsis, simultaneous activation of Nrf2 and FOXO3a cooperatively lowers ROS and inflammation in the heart (Hu et al., 2021). AMPK is another key protein. It keeps track of the cell’s energy. SIRT3 can turn on AMPK by raising the NAD⁺/NADH ratio and removing acetyl groups from LKB1 (Murugasamy et al., 2022). AMPK helps FOXO3a by adding phosphate groups to it. That makes FOXO3a work better with other proteins (Zhao and Liu, 2021). SIRT3 and AMPK cooperate to remove damaged mitochondria by inhibiting the mTOR pathway. FOXO3a raises Sesn2 levels, which activate AMPK and suppress mTOR (Xi et al., 2024). In septic cardiomyopathy, drugs that stimulate both AMPK and SIRT3 may provide stronger heart protection (Xu et al., 2020). In addition, SIRT3 and FOXO3a inhibit NF-κB, a protein that promotes inflammation, thereby reducing inflammatory signals and preventing further oxidative stress (Wu et al., 2022). 5 Experimental Studies on the Role of the SIRT3–FOXO3a Axis in Septic Cardiomyopathy 5.1 Functional validation in animal and cell models Many lab and animal studies have shown that the SIRT3–FOXO3a axis plays a big role in septic cardiomyopathy (SCM). In sepsis mice, those without SIRT3 had worse heart function after LPS treatment. Their heart pumping ability went down a lot, shown by lower ejection and shortening fractions (Xu et al., 2020). In normal mice, LPS also reduced SIRT3 levels in the heart and blocked FOXO3a from moving into the nucleus. Antioxidant enzyme levels dropped too (Xu et al., 2020). But when mice with sepsis were treated with Emodin-a compound that boosts SIRT3-their heart function got better. This benefit was gone in mice that didn’t have SIRT3, which shows the effect came from SIRT3 (Xu et al., 2020). In heart cells, adding SIRT3 or FOXO3a through plasmids helped lower ROS, protect mitochondria, and stop cell death caused by LPS (Xu et al., 2020). But when FOXO3a didn’t have the key spots where SIRT3 normally acts, this protection didn’t happen (Tyagi and Pugazhenthi, 2023). Also, when FOXO3a was knocked down, the good effects of SIRT3 were weaker (Figure 3) (Chang et al., 2019).
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