Figure 2.

Multifaceted regulatory mechanisms of SIRT3 in cellular homeostasis. (A) SIRT3 regulates autophagy through the deacetylation of FOXO1 and FOXO3a, which interact with E3 ligase and PARKIN to promote mitochondrial fission. Additionally, SIRT3 activates the LKB1/AMPK axis, thereby modulating autophagy via mTOR inhibition and Raptor activation, maintaining mitochondrial homeostasis and cellular integrity. Furthermore, SIRT3 influences mitochondrial dynamics by promoting the expression of MnSOD, thus alleviating oxidative damage caused by ROS. (B) SIRT3 suppresses pro-inflammatory signaling by deacetylating transcription factors NF-κB and AP-1, thereby attenuating NLRP3 inflammasome assembly and subsequent interleukin release. SIRT3 modulates the chemotactic proteins levels such as TGF-β1 in response to stress signals such as Ang-II. (C) In fibrosis, SIRT3 regulates the expression of fibrotic markers by deacetylating histone H3, thereby influencing gene transcription. It affects pathways related to extracellular matrix remodeling, including directly modulating TGF-β1 expression, a key driver of fibrosis. Metabolically, SIRT3 coordinates glycolysis, TCA cycle flux, and oxidative phosphorylation. by deacetylating key enzymes such as MnSOD, ensuring efficient energy production. By dynamically regulating mitochondrial protein acetylation, SIRT3 enables adaptive metabolic reprogramming during cellular stress.