International Journal of Clinical Case Reports, 2025, Vol.15, No.5, 239-247 http://medscipublisher.com/index.php/ijmms 239 Review and Progress Open Access The Role of the SIRT3–FOXO3a Axis in Mitochondrial Homeostasis and Oxidative Stress: Insights into Septic Cardiomyopathy Xiaohong Yang, Liting Wang Hainan Institute of Biotechnology, Haikou, 570206, Hainan, China Corresponding author: liting.wang@hibor.org International Journal of Molecular Medical Science, 2025, Vol.15, No.5 doi: 10.5376/ijccr.2025.15.0025 Received: 10 Aug., 2025 Accepted: 14 Sep., 2025 Published: 27 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: Yang X.H., and Wang L.T., 2025, The role of the SIRT3-FOXO3a axis in mitochondrial homeostasis and oxidative stress: insights into septic cardiomyopathy, International Journal of Clinical Case Reports, 15(5): 239-247 (doi: 10.5376/ijccr.2025.15.0025) Abstract Septic cardiomyopathy is a serious heart condition that often develops during sepsis. One main cause is oxidative stress, which damages mitochondria. This study focuses on the SIRT3–FOXO3a pathway and its role in heart protection. The pathway maintains mitochondrial function and limits oxidative injury. Studies show that SIRT3 activates FOXO3a by removing acetyl groups. Activated FOXO3a boosts the production of antioxidant proteins, which clear ROS, repair mitochondria, and improve cellular energy use. These effects help lessen damage to heart muscle. Experimental evidence indicates that activating this pathway can enhance heart performance, making it a potential target for new treatments. This study provides insights for novel therapies and supports a more personalized approach to treating septic cardiomyopathy. Keywords Septic cardiomyopathy; SIRT3; FOXO3a; Oxidative stress; Mitochondrial function; Autophagy regulation; Signaling pathway 1 Introduction Septic cardiomyopathy (SCM) happens when the heart cannot pump well during sepsis. It often shows weak heartbeats, larger heart chambers, and a low ejection fraction. The good news is that heart function can get better with proper treatment (Hollenberg and Singer, 2021; Zakynthinos et al., 2025). But SCM makes sepsis more dangerous. Studies report that 70%-90% of patients with septic shock and SCM may die (Murugasamy et al., 2022). SCM is not caused by just one reason. Many things may lead to it-too many inflammation signals, harm to mitochondria from nitric oxide (NO) and reactive oxygen species (ROS), problems with calcium, and nerve system issues (Qin et al., 2024). Among them, mitochondrial harm and oxidative stress are thought to be the main ones. During sepsis, inflammation reduces the mitochondrial membrane potential in heart cells. This makes less ATP and causes more ROS to build up. As a result, the heart cannot pump well (Murugasamy et al., 2022; Qin et al., 2024). The key question is: how can we keep mitochondria safe and cut down oxidative stress to help the heart in sepsis (Kokkinaki et al., 2019; Hou et al., 2024). Two proteins-SIRT3 and FOXO3a-are now getting attention in heart and aging research (Chaanine et al., 2016; Zhang et al., 2020b). SIRT3 lives in the mitochondria and removes acetyl groups from proteins. This helps cells use energy, survive stress, and resist damage (Tyagi and Pugazhenthi, 2023). FOXO3a is a gene regulator. It is sometimes called a “longevity factor” because it turns on genes that fight ROS, clean up damaged cell parts, and prevent cell death (Chang et al., 2019; Zhao and Liu, 2021). SIRT3 and FOXO3a work in coordination. By removing acetyl groups from FOXO3a, SIRT3 activates it. Once activated, FOXO3a triggers antioxidant genes like CAT and SOD2, which help eliminate ROS and protect cells from stress (Wu et al., 2022; Velpuri et al., 2024). This cooperation, called the SIRT3–FOXO3a axis, preserves mitochondrial health and reduces oxidative injury. During sepsis, toxins and inflammation damage heart cells, and researchers suggest this axis may safeguard the heart in SCM by maintaining proper mitochondrial function (Wu et al., 2022; Tyagi and Pugazhenthi, 2023).
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