International Journal of Clinical Case Reports, 2025, Vol.15, No.5, 239-247 http://medscipublisher.com/index.php/ijmms 241 Under stress, Akt becomes inactive, allowing proteins like JNK to activate FOXO3a, which then enters the nucleus (Zhao and Liu, 2021). In the nucleus, FOXO3a binds to DNA and triggers stress-response genes such as CAT, SOD2, and Gadd45 (Chang et al., 2019). It also upregulates autophagy genes like LC3B and Bnip3, aiding in the removal of damaged mitochondria (Xi et al., 2024). This is important in heart cells, which divide very little. FOXO3a helps these cells survive stress for a long time. It may also slow heart aging and enlargement (Schips et al., 2011; Deng et al., 2021). In mice without FOXO3a, heart damage from stress is worse. But when FOXO3a is more active, it raises Catalase and SOD2, lowers ROS, and protects the heart (Chang et al., 2019). 2.3 Mechanistic Analysis of SIRT3-FOXO3a Coupling SIRT3 and FOXO3a work closely as a team. They form a key pathway that helps control redox balance and keep mitochondria healthy (Jacobs et al., 2008; Yu et al., 2017). (1) SIRT3 activates FOXO3a by deacetylation SIRT3 can attach to FOXO3a and remove its acetyl groups. This makes FOXO3a more stable and more effective at turning on gene activity. When there’s more SIRT3 in the cell, more FOXO3a gets deacetylated. Then FOXO3a moves into the nucleus and starts turning on antioxidant genes (Xian et al., 2025). SIRT3 acts on FOXO3a at spots such as K271 and K290. This helps make more MnSOD and Catalase, two key antioxidant proteins (Figure 2) (Tyagi and Pugazhenthi, 2023). Figure 2 SIRT3 regulates antioxidant stress responses and mitochondrial homeostasis through deacetylation and activation of FOXO3a (Adapted from Wu et al., 2022) (2) FOXO3a boosts the effect of SIRT3 After activation, FOXO3a cooperates with SIRT3 to safeguard cells. It activates genes that lower ROS levels and stimulate mitophagy to remove damaged mitochondria. If SIRT3 is missing, FOXO3a can’t do this job well. As a result, damaged mitochondria start to pile up. But when the SIRT3-FOXO3a pathway starts working again, heart
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