Relevance and application of sirtuin 3-activated mitophagy in gastric cancer treatment

Figure 4 Conventional negative and positive regulatory mechanism of sirtuin 3. A: Conventional negative regulatory mechanism of sirtuin 3 (SIRT3). In the hypoxic microenvironment, hypoxia-inducible factor-1α (HIF-1α) selectively activates glycolysis-related enzymes and inhibits mitochondrial SIRT3 to block the tricarboxylic acid cycle – a hallmark of the classic "Warburg effect". This process drives local reactive oxygen species accumulation and amplifies inflammatory cascades, worsening hypoxia and creating a negative feedback loop targeting SIRT3. Notably, activating SIRT3 can suppress hypoxia-induced HIF-1α overexpression through specific mechanisms, thereby disrupting the sustained activation of this closed negative regulatory loop; B: Conventional positive regulatory mechanism of SIRT3. SIRT3-AMP-activated protein kinase-peroxisome proliferator-activated receptor γ coactivator 1α-SIRT3 positive feedback loop represents a key pathway for SIRT3's positive regulation. AMPK: AMP-activated protein kinase; ATP: Adenosine triphosphate; FoxO3a: Forkhead box protein O3a; HIF-1α: Hypoxia-inducible factor-1α; ROS: Reactive oxygen species; SIRT3: Sirtuin 3; SUMO: Small ubiquitin-related modifier; TCA: Tricarboxylic acid; PGC-1α: Peroxisome proliferator-activated receptor γ coactivator 1α.