International Journal of Clinical Case Reports, 2025, Vol.15, No.5, 239-247 http://medscipublisher.com/index.php/ijmms 244 Figure 3 Validation of the protective role of the SIRT3-FOXO3a pathway in septic cardiomyopathy models (Adapted from Chang et al., 2019) In mice that were missing FOXO3a, sepsis caused more damage to the heart. But when FOXO3a was added back, the heart injury was reduced (Chang et al., 2019). All these results show that SIRT3 and FOXO3a must work together to protect the heart during sepsis. They help lower ROS, keep mitochondria working, and stop heart cells from dying. So, turning on this pathway could be a good way to treat SCM. 5.2 Progress in interventional strategies targeting the axis Because this axis helps protect the heart, researchers are looking for ways to target it. One way is by using compounds that boost SIRT3. For example, Emodin raised SIRT3 levels in septic mice. This helped FOXO3a move into the nucleus and improved heart function (Xu et al., 2020). Honokiol is another compound that decreases acetylation in heart cells, enhances MnSOD activity, and improves cardiac pumping under stress (Peng et al., 2024). Yet, in SIRT3-deficient mice, these effects were absent, indicating its action relies on SIRT3 (Xu et al., 2020). Another idea is to directly activate FOXO3a. Using AAV vectors to add more FOXO3a increased antioxidant and autophagy responses in the heart, and this reduced damage markers (Chang et al., 2019). But if SIRT3 wasn’t also activated, the results were not as strong (Tyagi and Pugazhenthi, 2023). Some studies also tested combo treatments. Giving both Honokiol and a low dose of Metformin worked better than using either one alone. This combo helped reduce heart injury and inflammation in sepsis (Xu et al., 2020).
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