International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 244-252 http://medscipublisher.com/index.php/ijccr 251 In preclinical models, activating SIRT3 with drugs or increasing its expression through genes, as well as subsequently enhancing the activities of FOXO3a and SOD2, have all demonstrated significant protective effects. In sepsis models, intervention methods such as resveratrol, emoticon treatment and SIRT3 overexpression have been proven to restore mitochondrial function, reduce oxidative stress, inhibit pyroptosis, increase survival rates and improve organ function, highlighting the potential of targeting this signaling axis for treatment. Although the evidence from animal experiments is very convincing, there are still considerable difficulties in applying it to patients. Future work should focus on integrating basic research with clinical exploration to identify reliable disease markers and arrange well-designed trials to verify the safety and practical efficacy of those treatment methods targeting sirt3-foxo3a-sod2 in patients with sepsis. Making up for this deficiency is of great significance for fully realizing the application value of this signal network in the treatment of sepsis. Acknowledgments We would like to thank Mr. Sun continuous support throughout the development of this study. Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Chang G., Chen Y., Zhang H., and Zhou W., 2019, Trans sodium crocetinate alleviates ischemia/reperfusion-induced myocardial oxidative stress and apoptosis via the SIRT3/FOXO3a/SOD2 signaling pathway, International Immunopharmacology, 71: 361-371. https://doi.org/10.1016/j.intimp.2019.03.056 Fan H., Sun M., and Zhu J., 2025, S-nitrosoglutathione inhibits pyroptosis of kidney tubular epithelial cells in sepsis via the SIRT3/SOD2/mtROS signaling pathway, Renal Failure, 47(1): 2472987. https://doi.org/10.1080/0886022X.2025.2472987 Fu B., Zhao J., Peng W., Wu H., and Zhang Y., 2017, Resveratrol rescues cadmium-induced mitochondrial injury by enhancing transcriptional regulation of PGC-1α and SOD2 via the Sirt3/FoxO3a pathway in TCMK-1 cells, Biochemical and Biophysical Research Communications, 486(1): 198-204. https://doi.org/10.1016/j.bbrc.2017.03.027 Gao J., Feng Z., Wang X., Zeng M., Liu J., Han S., Xu J., Chen L., Cao K., Long J., Li Z., Shen W., and Liu J., 2017, SIRT3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress, Cell Death and Differentiation, 25: 229-240. https://doi.org/10.1038/cdd.2017.144 Gong S., Chen H., Fang S., Li M., Hu J., Li Y., Yu B., Kou J., and Li F., 2025, Ginsenoside Rh1 mitigates mitochondrial dysfunction induced by myocardial ischaemia through its novel role as a sirtuin 3 activator, British Journal of Pharmacology, 182: 3017-3035. https://doi.org/10.1111/bph.70022 Jiang H., Zhang Y., Ji P., Ming J., Li Y., and Zhou Y., 2025, Surfactant protein D alleviates chondrocytes senescence by upregulating SIRT3/SOD2 pathway in osteoarthritis, Molecular Medicine, 31(1): 161. https://doi.org/10.1186/s10020-025-01221-6 Qiao L., Lin X., Liu H., Xiang R., Zhan J., Deng F., Bao M., He H., Wen X., Deng H., Wang X., He Y., Yang Z., and Han J., 2024, T-2 toxin induces cardiac fibrosis by causing metabolic disorders and up-regulating Sirt3/FoxO3α/MnSOD signaling pathway-mediated oxidative stress, Journal of Environmental Sciences, 150: 532-544. https://doi.org/10.1016/j.jes.2024.03.001 Qin X., Cai P., Liu C., Chen K., Jiang X., Chen W., Li J., Jiao X., Guo E., Yu Y., Sun L., and Tian H., 2023, Cardioprotective effect of ultrasound-targeted destruction of Sirt3-loaded cationic microbubbles in a large animal model of pathological cardiac hypertrophy, Acta Biomaterialia, 164: 604-625. https://doi.org/10.1016/j.actbio.2023.04.020 Shehata A., Anter A., and Ahmed A., 2023, Role of SIRT1 in sepsis‐induced encephalopathy: molecular targets for future therapies, European Journal of Neuroscience, 58: 4211-4235. https://doi.org/10.1111/ejn.16167 Sundaresan N., Gupta M., Kim G., Rajamohan S., Isbatan A., and Gupta M., 2009, Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice, The Journal of Clinical Investigation, 119(9): 2758-2771. https://doi.org/10.1172/JCI39162 Wang J., Li W., Zhao F., Han Q., Shan L., and Qian Y., 2023, Sirt3 regulates NLRP3 and participates in the effects of plantainoside D on acute lung injury sepsis, Aging, 15: 6710-6720. https://doi.org/10.18632/aging.204628 Wu Z., Wang Y., Lu S., Yin L., and Dai L., 2023, SIRT3 alleviates sepsis-induced acute lung injury by inhibiting pyroptosis via regulating the deacetylation of FoxO3a, Pulmonary Pharmacology and Therapeutics, 82: 102244. https://doi.org/10.1016/j.pupt.2023.102244
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