糖尿病、肥胖和脂肪肝病等代谢性疾病已成为全球性的流行病。这些疾病的发病机制涉及葡萄糖稳态失衡、脂质代谢紊乱、能量平衡失调和炎症反应等系统性紊乱，然而针对这些核心紊乱的有效治疗策略仍然有限。沉默信息调节因子3（SIRT3）是一种主要的线粒体去乙酰化酶，作为核心调节因子，它能够启动代谢稳态的协同代偿调控机制，我们将其定义为“头雁分子”。SIRT3的激活可启动“负熵机制”，通过增强胰岛素敏感性、促进脂质氧化代谢、维持氧化还原稳态、重塑能量代谢、抑制炎症反应等多维度协同机制，对抗机体全身性代谢紊乱。本文还评估了天然产物、合成化合物及NAD⁺前体作为SIRT3激活剂的治疗潜力，并强调其作为安全、可持续治疗方案的广阔前景。本综述明确了SIRT3作为核心调节因子的关键作用，并提出以其为靶点重建系统性代谢稳态的策略。

Metabolic diseases, such as diabetes, obesity, and steatotic liver disease, represent a global epidemic. The pathogenesis of these disorders involves systemic disturbances in glucose homeostasis, lipid metabolism, energy balance, and inflammation, yet effective therapeutic strategies to correct these core disturbances remain limited. Silent information regulator 3 (sirtuin 3 (SIRT3)), a major mitochondrial deacetylase that we defined as the “head goose molecule,” acts as a central regulator and can initiate a coordinated rescue of metabolic homeostasis. We integrate evidence that SIRT3 activation triggers a “negentropic mechanism,” a suite of processes that collectively counteract systemic metabolic disorders by enhancing insulin sensitivity, promoting lipid oxidation, fine-tuning redox equilibrium, optimizing energy expenditure, and suppressing inflammation. The therapeutic potential of SIRT3 activators derived from natural products, synthetic compounds, and nicotinamide adenine dinucleotide (NAD⁺) precursors is evaluated, highlighting their promise as safe and sustainable treatment options. This review establishes the role of SIRT3 as a master regulator and suggests that it should be targeted to reconstitute systemic metabolic homeostasis.