Activation of Sirtuin 3, a Promising “Head Goose Molecule,” Triggers the Negentropic Mechanism for Treating Metabolic Diseases

Hu Li , Tong Wang , Biao Dong , Zonggen Peng , Jiandong Jiang

Engineering ›› 2026, Vol. 60 ›› Issue (5) : 294 -309.

PDF (2513KB)
Engineering ›› 2026, Vol. 60 ›› Issue (5) :294 -309. DOI: 10.1016/j.eng.2025.12.008
Research
research-article
Activation of Sirtuin 3, a Promising “Head Goose Molecule,” Triggers the Negentropic Mechanism for Treating Metabolic Diseases
Author information +
History +
PDF (2513KB)

Abstract

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.

Graphical abstract

Keywords

Sirtuin 3 / Metabolic diseases / Head goose molecule / Negentropic mechanism / Sirtuin 3 activator

Cite this article

Download citation ▾
Hu Li, Tong Wang, Biao Dong, Zonggen Peng, Jiandong Jiang. Activation of Sirtuin 3, a Promising “Head Goose Molecule,” Triggers the Negentropic Mechanism for Treating Metabolic Diseases. Engineering, 2026, 60 (5) : 294-309 DOI:10.1016/j.eng.2025.12.008

登录浏览全文

4963

注册一个新账户 忘记密码

1. Introduction

Metabolic diseases include a range of disorders characterized by metabolic abnormalities, most notably diabetes, obesity, steatotic liver disease, cardiovascular disease, and associated metabolic syndromes [1], [2]. Over the past two decades, the global prevalence of metabolic diseases has increased significantly, affecting one-quarter of the worldwide population, and is predicted to increase further in the future [3], [4]. Complex and shared molecular mechanisms, including interactions between glucose metabolism and lipid metabolism, energy metabolism, inflammation, and oxidative stress, are often responsible for the occurrence and development of metabolic diseases [5], [6], [7], [8]. Glucose metabolism disorders and insulin resistance are key mechanisms underlying many metabolic diseases. When the cellular response to insulin decreases, blood glucose levels increase, leading to increased insulin secretion, which can ultimately result in pancreatic failure [9]. Mitochondrial dysfunction can lead to excessive fatty acid accumulation, further disrupting glucose and lipid metabolism and energy homeostasis [5], [10]. Oxidative stress, which is primarily associated with mitochondrial energy disorders, further exacerbates metabolic abnormalities by damaging cells and disrupting cellular signaling [6]. Chronic low-grade inflammation and immune cell infiltration associated with metabolic syndrome can also influence insulin signaling pathways, accelerating disease progression [11]. The complexity of metabolic diseases stems from the multifaceted interplay of genetic predispositions, environmental factors, and the gut microbiota, ultimately leading to a state of systemic biological disorder [12], [13]. This progression can be viewed through the law of “entropy increase,” a concept from physics, denoting the increase in systemic chaos that drives disease deterioration [14], [15], [16], [17]. To quantitatively assess this metabolic chaos and overcome the challenges of histopathological heterogeneity, we first employed Shannon entropy to evaluate the efficacy of classic drugs such as berberine (BBR) and metformin, which is based on its prior success in assessing skin disease severity and metabolic syndrome risk [15], [18], [19]. Shannon entropy thus offers a potent and objective tool for evaluating interventions in highly heterogeneous metabolic diseases.

The treatment of metabolic diseases has become a public health challenge. Diseases such as obesity and type 2 diabetes mellitus (T2DM) require comprehensive treatment strategies because of their complicated pathogenesis [20], [21]. First-line treatments include lifestyle interventions such as dietary control and increased physical activity. However, patients often struggle to maintain these lifestyle changes [22]. Drug treatments are primarily reserved for severe cases and face several obstacles, as they usually only mitigate symptoms, and no highly effective solutions or single medications that can address most problems have been discovered [23], [24], [25], [26]. On the basis of our experience in pharmacological research and drug discovery [27], [28], [29], we propose that treating metabolic diseases with complex pathogenic mechanisms requires a systemic approach to regulate multiple signaling pathways through a central or key molecule. Therefore, we have introduced the concept of the “head goose molecule” [30], analogous to a lead goose guiding its flock in migration. An “head goose molecule” can control downstream effectors to systematically remedy dysfunctional pathogenesis. The intricate mechanisms and drug development challenges associated with metabolic diseases undoubtedly require effective and safe “head goose molecule” as front-runners to reprogram cellular networks and effectively suspend or reverse disease progression.

In long-term studies of pharmacological treatments for metabolic diseases, we identified silent information regulator 3 (sirtuin 3 (SIRT3)), a key regulator of mitochondrial function, as a direct target of the multieffect drug BBR [31]. As a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, SIRT3 has a conserved catalytic core structure comprising two distinct domains: a large Rossmann-fold domain that facilitates NAD+ binding and a smaller zinc-binding domain responsible for substrate recognition (Fig. 1(a)) [32]. Through posttranslational deacetylation of various mitochondrial substrates, SIRT3 benefits essential metabolic disorders, such as diabetes mellitus, obesity, and hepatic steatosis. This highlights its potential as a promising therapeutic target for metabolic diseases. However, the translation of SIRT3 into a therapeutic target still presents challenges. These challenges include the potential for context-dependent and even contradictory roles of SIRT3 in different disease stages or tissues, the complexity of its regulation by NAD+ levels and upstream signals, and the current lack of specific and potent SIRT3 activators suitable for clinical use.

This review aims to systematically summarize the evidence establishing SIRT3 as a pivotal “head goose molecule” that can trigger a negentropic mechanism-coordinated reversal of metabolic disorders by improving glucose homeostasis, lipid metabolism, energy balance, and inflammatory responses. We will critically evaluate the therapeutic potential of pharmacological SIRT3 activation, explicitly address the current challenges and limitations in the field, and provide a balanced perspective on the prospects of targeting SIRT3 for the systemic management of metabolic diseases.

2. SIRT3 appears to be a promising “head goose molecule” for inducing negentropy to improve metabolic diseases

In contrast to the mechanism of “entropy increase” observed in metabolic diseases, negentropy refers to the systematic remediation of dysfunctional pathogenesis, in which regulatory networks are organized in an orderly fashion [16], [30]. By investigating key regulatory molecules involved in glucose and lipid metabolism, energy metabolism, inflammatory responses, and oxidative stress, as well as the mechanisms of multieffect drugs, such as BBR and metformin [33], [34], we identified SIRT3 as a potential “head goose molecule.” The sirtuin family (SIRT1-7) is a class III histone deacetylase whose acetylated group is removed from the N-acetyllysine residues of histones or nonhistone proteins. They possess an NAD+-binding catalytic domain and require NAD+ as a cofactor to act on various substrates. All SIRTs contain N-terminal, catalytic core, and C-terminal structures of varying lengths (Fig. 1(b)). Notably, SIRT3, SIRT4, and SIRT5 possess an additional mitochondrial targeting sequence at the N-terminus, enabling their localization in mitochondria. Deacetylation activity is the predominant physiological role of SIRTs in metabolic regulation, with SIRT1, SIRT2, and SIRT3 exhibiting robust deacetylase activity, whereas other SIRTs display only weak activity (Fig. 1(c)). Similar to sirtuin-mediated epigenetic control in cancer through deacetylation [35], SIRT3 orchestrates multiple key molecules in metabolic pathways through deacetylation, thereby playing a “head goose” role in regulating the progression of nontumor metabolic diseases.

The role of SIRTs in metabolic diseases has been extensively studied (Table 1 [33], [34], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53]). This review focuses on nontumor metabolic contexts, given the documented beneficial and harmful roles of SIRTs in cancer [54], [55]. Among all SIRTs, SIRT1, SIRT3, and SIRT6 are the most extensively studied in metabolic diseases, whereas the others are less frequently investigated [34], [56], [57]. SIRT1 and SIRT2 are generally protective against obesity and hepatic steatosis [34] but play dual roles in diabetes. For example, Sirt1 knockdown enhances hepatic insulin sensitivity and reduces fasting hyperglycemia in diabetic rats [36], whereas its downregulation impairs insulin signaling and glucose uptake in adipocytes [37]. Similarly, SIRT2 promotes hepatic glucose uptake by deacetylating the glucokinase regulatory protein at K126 [34], [38], but its downregulation improves glucose uptake in insulin-resistant Neuro 2a cells [58]. SIRT4 has detrimental effects on obesity and fatty liver disease. Its upregulation in nonalcoholic fatty liver disease (NAFLD) patients reduces fatty acid oxidation and promotes ectopic lipid storage [39]. Conversely, knocking down Sirt4 in mouse liver alleviates NAFLD by suppressing mitochondrial trifunctional protein (MTP)-mediated fatty acid oxidation [39]. Sirt4 also plays a contradictory role in insulin resistance; its knockdown enhances glucose-stimulated insulin secretion [40], but it also promotes insulin secretion through adenine nucleotide translocase 2 (ANT2) inhibition and elevated adenosine triphosphate (ATP) levels [39]. SIRT5 improves obesity and hepatic steatosis; however, its high expression is correlated with elevated blood glucose levels. SIRT5 inhibition promotes pancreatic β-cell proliferation and insulin secretion, suggesting a role in the development of T2DM [41]. SIRT6 has conflicting glucoregulatory effects; SIRT6 improves glucose homeostasis in transgenic mice but also suppresses insulin signaling by targeting insulin receptor substrate (IRS)-1, IRS-2, and protein kinase B [42]. SIRT7 disrupts normal glucose and lipid metabolism by targeting specific sites in white/brown adipose tissue as well as the liver [34], [42]. Therefore, the sirtuin family, apart from SIRT3, demonstrates both beneficial and harmful effects and even has dual functions in metabolic diseases such as diabetes mellitus, obesity, and hepatic steatosis.

3. The negentropic mechanism of SIRT3 in metabolic diseases

SIRT3 is predominantly localized in eukaryotic mitochondria, where it interacts with at least 84 mitochondrial proteins, suggesting its close association with multiple human diseases characterized by mitochondrial dysfunction [59]. In contrast to other members of the sirtuin family (Table 1), SIRT3 consistently exhibits protective effects throughout the pathogenesis of metabolic diseases, including glucose homeostasis, lipid metabolism, energy balance, and inflammation [33], [55], [60]. Many studies have demonstrated a causal relationship between SIRT3 deficiency and pathological conditions such as diabetes, cardiovascular disease, and obesity [61], [62]. These findings support our hypothesis that SIRT3 functions as a “head goose molecule” capable of initiating a negentropic mechanism to address systemic metabolic disorders in the body (Fig. 2).

3.1. Role of SIRT3 in glucose homeostasis

Glucose homeostasis is intricately linked to metabolic diseases. SIRT3 orchestrates glucose metabolism by ameliorating insulin resistance, optimizing glucose utilization, regulating glycolytic flux, and promoting gluconeogenesis, primarily through the deacetylation of key enzymes in various tissues (Fig. 3).

In diabetic and obese animal models, SIRT3 enhances insulin signaling via the deacetylation of acetyl-coenzyme A (CoA) synthetase 2 (AceCS2). This posttranslational modification activates AceCS2, promotes the conversion of acetate to acetyl-CoA, replenishes mitochondrial acetyl-CoA pools, and stimulates the tricarboxylic acid (TCA) cycle and ATP synthesis [63], [64]. The resulting energy surplus helps reverse insulin resistance in hepatocytes and skeletal muscle [65]. Sirt3 knockdown in myoblasts increases reactive oxygen species (ROS) levels, activates c-Jun N-terminal kinase (JNK) and IRS-1, and impairs insulin signaling, underscoring its role in improving hyperglycemia in diabetes [66]. SIRT3 also optimizes glucose utilization. For example, SIRT3 promotes glucose uptake by upregulating the expression of the glucose transporters GLUT1 and GLUT4 in cardiomyocytes under diabetic energy stress [65]. SIRT3 also increases pyruvate flux into the TCA cycle in renal fibrosis by deacetylating the E1 component subunit-α of pyruvate dehydrogenase and isocitrate dehydrogenase 2 (IDH2), thereby enhancing mitochondrial glucose oxidation [67], [68]. In diffuse large B-cell lymphoma, SIRT3 activates glutamate dehydrogenase (GDH) to enhance the TCA cycle and cellular metabolism [60]. With respect to the regulation of glycolysis, SIRT3 has dual effects under different pathological and physiological conditions. In diabetic cardiomyopathy, SIRT3 upregulates 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) via the apelin pathway, promotes tumor protein 53 (p53) deacetylation, and inhibits p53-induced glycolysis regulatory phosphatase (TIGAR), collectively increasing fructose-2,6-bisphosphate levels to activate phosphofructokinase 1 (PFK1) and enhance glycolytic flux [61], [69]. Under energy deprivation, decreased ATP levels trigger SIRT3-mediated adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, which promotes glucose uptake and the activation of glycolytic enzymes, ensuring rapid energy replenishment [60].

Conversely, in cancer models, SIRT3 suppresses glycolysis and tumor growth through multiple mechanisms. First, SIRT3 reduces ROS production, stabilizes prolyl hydroxylase (PHD), and promotes hypoxia-inducible factor-1α (HIF-1α) degradation, downregulating HIF-1α-dependent glycolytic gene expression and lactate production [70], [71]. Second, SIRT3 deacetylates cyclophilin D (cypD) to dissociate hexokinase II (HKII) from mitochondria, uncoupling glycolysis from oxidative phosphorylation [60]. In addition, SIRT3 stabilizes p53 by deacetylating phosphatase and tensin homolog (PTEN), inhibiting murine double minute2 (MDM2)-mediated nuclear export and degradation and promoting the accumulation of p53 to activate pro-apoptotic signals. Accumulated p53 also controls metabolism by downregulating critical components of the glycolytic machinery at the transcriptional level [60], [72]. SIRT3 also suppresses the Warburg effect by deacetylating glutamate oxaloacetate transaminase 2 (GOT2), downregulating the expression of glycolytic genes such as Glut1 and lactate dehydrogenase A (Ldha), and redirecting metabolism toward oxidative phosphorylation [65], [73]. During fasting, SIRT3 promotes gluconeogenesis by deacetylating ornithine transcarbamylase (OTC), facilitating amino acid-derived glucose synthesis and preventing ammonia accumulation. Liver-specific Sirt3 knockout (KO) mice exhibit hypoglycemia and lethal hyperammonemia, underscoring the physiological necessity of this pathway [74]. SIRT3 also deacetylates and activates 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) to increase β-hydroxybutyrate (β-HB) production, supporting energy maintenance during fasting [75].

3.2. Role of SIRT3 in lipid metabolism

Dysregulated lipid metabolism is a key factor in obesity, NAFLD, and insulin resistance. SIRT3 plays a crucial role in maintaining lipid balance through various regulatory mechanisms, including promoting fatty acid oxidation (FAO), inhibiting lipogenesis, and enhancing lipid droplet autophagy (Fig. 4).

Long-chain acyl-CoA dehydrogenase (LCAD) is a rate-limiting enzyme in FAO and catalyzes the initial step of dehydrogenation [76]. In the absence of SIRT3, increased lysine 42 acetylation in LCAD leads to excessive accumulation of hepatic triglycerides and fatty acid metabolism intermediates, resulting in myocardial hypertrophy and possibly heart failure [73]. In contrast, SIRT3 positively regulates LCAD expression via deacetylation, increasing enzyme activity and promoting FAO [73]. Similarly, SIRT3 deacetylates MTP, restoring FAO and improving NAFLD in high-fat diet (HFD)-fed mice [77]. Very-long-chain acyl-CoA dehydrogenase (VLCAD) is also activated by SIRT3-mediated deacetylation at lysine 507, enhancing FAO and stabilizing its membrane localization via cardiolipin binding. SIRT3 deficiency in mice impairs this interaction, compromising FAO and contributing to metabolic diseases [78]. During prolonged fasting, SIRT3 deacetylates heat shock protein 10 (Hsp10) at lysine 56 to stabilize the Hsp10-Hsp60 chaperone complex, which maintains medium-chain acyl-CoA dehydrogenase (MCAD) activity and optimizes β-oxidation [79]. In the ischemic heart, SIRT3 inactivates acetyl-CoA carboxylase (ACC) via deacetylation, lowering malonyl-CoA levels, relieving carnitine palmitoyltransferase 1 (CPT1) inhibition, and facilitating mitochondrial fatty acid uptake for β-oxidation [80], [81]. Reduced malonyl-CoA also indirectly inhibits de novo fatty acid synthesis [82]. Moreover, SIRT3 deacetylates enoyl-CoA hydratase 1 (ECHS1), restoring its activity in oxidizing fatty acids and branched-chain amino acids, reducing oncogenic metabolite accumulation, and inhibiting mechanistic target of rapamycin (mTOR)-driven carcinogenesis under nutrient overload [83].

SIRT3 also suppresses lipogenesis through the deacetylation-mediated activation of liver kinase B1 (LKB1), which subsequently triggers AMPK signaling. This cascade downregulates the transcription of key lipogenic enzymes, including ACC and fatty acid synthase (FAS), thereby reducing lipid synthesis [84]. In HFD-fed Sirt3 KO mice, cardiac lipotoxicity is exacerbated, indicating that SIRT3 plays a protective role against lipid overload [61]. Notably, SIRT3 also maintains lipid droplet homeostasis via AMPK-dependent autophagy. For example, in NAFLD models, SIRT3 overexpression enhances phosphorylated AMPK and autophagy, reducing hepatic lipid accumulation and lipotoxicity. Conversely, Sirt3 KO impairs mitophagy and worsens hepatic steatosis, underscoring the therapeutic potential of this axis [62].

3.3. Role of SIRT3 in energy balance

Energy homeostasis is essential for physiology, and its dysregulation underlies numerous metabolic disorders. SIRT3 maintains this balance through three interconnected mechanisms: ATP optimization, redox regulation, and mitochondrial plasticity (Fig. 5).

SIRT3 generally increases ATP production by deacetylating key enzymes involved in energy metabolism. Sirt3 KO mice exhibit more than 50% reduced basal ATP levels in metabolically active tissues, accompanied by hyperacetylation of ATP synthase and impaired exercise tolerance [59], [65], [76]. In HFD-induced T2DM mice, SIRT3 downregulation in skeletal muscle leads to hyperacetylation of ATP synthase subunit O (ATP5O) at histidine 135, decreasing electron transport chain (ETC) efficiency and ATP synthesis and accelerating insulin resistance and hyperglycemia. SIRT3 also deacetylates nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase subunit A9 (NDUFA9) and complex II (SDHA), increasing NADH oxidation and succinate-driven respiration [73], [85]. Paradoxically, excessive SIRT3 activity can impair bioenergetics by deacetylating mitochondrial ribosomal protein L10 (MRPL10), disrupting ribosome assembly, suppressing the synthesis of oxidative phosphorylation (OXPHOS) subunits and ATP production, and exacerbating neuronal dysfunction in Alzheimer’s disease models [86].

In redox regulation, the crosstalk between SIRT3 and AMPK forms a redox-sensitive feedback loop. AMPK inhibition diminishes SIRT3-mediated ROS suppression in hyperglycemic models, suggesting that AMPK acts downstream to amplify the antioxidant effects of SIRT3 [87]. Furthermore, SIRT3 maintains mitochondrial redox homeostasis by deacetylating and activating antioxidant enzymes such as superoxide dismutase 2 (SOD2 and MnSOD), IDH2, and peroxiredoxin 3 (PRDX3) through two mechanisms: direct deacetylation and forkhead box protein O3 (FoxO3a)-mediated transcriptional upregulation. In cardiac ischemia‒reperfusion injury, SIRT3 deficiency worsens oxidative stress and apoptosis, whereas its overexpression reduces infarct size by enhancing ROS clearance, highlighting its therapeutic potential in cardiovascular and metabolic diseases [88].

SIRT3 also regulates mitochondrial plasticity by modulating fission/fusion dynamics, mitophagy, and biogenesis. SIRT3 deacetylates optic atrophy 1 (OPA1) to promote mitochondrial fusion and cristae integrity, a mechanism that is impaired in patients with cardiac hypertrophy [89]. SIRT3 also activates the PINK1-Parkin mitophagy axis, upregulating B cell lymphoma 2 (BCL2)-interacting protein 3 (BNIP3), BNIP3-like protein X (NIX), and microtubule-associated protein 1 light chain 3 (LC3-II) to clear damaged organelles. Diabetic mice with Sirt3 knockdown develop cardiac hypertrophy because of defective mitophagy, highlighting the role of SIRT3 in adaptation to metabolic stress [90], [91]. Additionally, SIRT3 deacetylates FoxO3a to activate proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and mitochondrial transcription factor A (TFAM), promoting mitochondrial DNA (mtDNA) replication and ETC protein synthesis [92], [93]. This coordinated triad of mitochondrial dynamics, mitophagy-mediated quality control, and biogenesis-driven renewal, regulated by SIRT3, collectively protects the robustness of the mitochondrial network from metabolic stress-induced dysfunction.

3.4. Role of SIRT3 in inflammation

Chronic inflammation, a hallmark of metabolic disorders, arises from dysregulated immune responses that disrupt redox homeostasis and exacerbate tissue dysfunction. Preclinical and clinical evidence highlights the ability of SIRT3 to suppress inflammation by inhibiting the activation of inflammatory cells and cytokine production (Fig. 6).

At the cellular level, SIRT3 reprograms immune responses to restrict inflammatory cell activation. Specifically, SIRT3 promotes M2 macrophage polarization, shifting the balance from proinflammatory to anti-inflammatory phenotypes, as indicated by the increased infiltration of inflammatory cells in SIRT3-deficient mice [34]. This anti-inflammatory reprogramming is further reinforced by the SIRT3-mediated increase in mitochondrial antioxidant enzymes such as SOD2 [94], which reduces ROS accumulation, suppresses MAPK signaling, and alleviates lipopolysaccharides (LPS)-induced macrophage hyperactivation [34], [95].

SIRT3 also suppresses key cytokines via deacetylation-dependent mechanisms. In aortic endothelial cells, SIRT3 activates peroxisome proliferator-activated receptor alpha (PPAR-α) to upregulate endothelial nitric oxide synthase (eNOS) and suppress inducible nitric oxide synthase (iNOS), thereby attenuating vascular injury [96]. Furthermore, SIRT3 suppresses the nucleotide-binding oligomerization domain (NOD)-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, an effect that is particularly important in early metabolic disease for preventing vascular inflammation via upregulation of autophagy. SIRT3 also reduces the expression of the downstream cytokines interleukin (IL)-1β and IL-18 in hyperlipidemic-induced inflammation and vascular endothelial dysfunction, countering sustained inflammation in later disease stages [97], [98]. In cardiac inflammation and fibrosis models, SIRT3 deacetylates nuclear factor kappa B (NF-κB) subunits to attenuate proinflammatory cytokine transcription [99]. Notably, SIRT3 also disrupts the ROS-MAPK-NF-κB axis in free fatty acid-induced renal tubulointerstitial inflammation, underscoring its role in mitigating metabolic stress-driven organ damage [98], [100].

Therefore, the regulatory network of SIRT3 is a multitargeted “guardian” molecule that integrates metabolic adaptation with anti-inflammatory signaling, offering transformative potential for addressing the inflammatory underpinnings of metabolic diseases.

In summary, on the basis of the functions and mechanisms of SIRT3 described above, we consider SIRT3 a suitable “head goose molecule” that guides many substrates and targeted molecular networks, which we refer to as detailed negentropic mechanisms. This regulatory network, termed the negentropic mechanism, counteracts the biological entropy increase associated with metabolic diseases. These molecules and pathways are complex and significantly overlap with metabolism-related regulatory molecules, providing a strong basis for the belief that SIRT3 can serve as a lead molecule in reprogramming the biological entropy increase of metabolic diseases [34].

4. Activators of SIRT3 have potential for the treatment of metabolic diseases

The pivotal role of SIRT3 in mitigating metabolic disorders highlights the therapeutic promise of its activators. Unlike specific inhibitors, SIRT3 activators often produce milder, more physiologically tuned responses because of feedback within downstream pathways, making them particularly suitable for long-term management of chronic conditions. A primary challenge, however, is achieving isoform selectivity, given the structural conservation among sirtuins [33]. Notably, tissue-specific expression, distinct subcellular localization, and the recent identification of unique structural pockets in SIRT3 offer promising avenues for developing targeted drugs [101]. SIRT3 activity is also associated with NAD+ availability, genetic background, and disease state, leading to therapeutic variability across patient subgroups. Therefore, precise identification of SIRT3-specific binding sites and the development of highly selective activators are essential for minimizing off-target effects and enabling personalized therapies. The following sections discuss SIRT3 activators, categorized as natural products, synthetic compounds, and NAD+ precursors, with an emphasis on their mechanisms of action and clinical significance (Fig. 7 and Table 2 [31], [33], [65], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155], [156], [157], [158], [159], [160], [161], [162], [163], [164], [165]).

4.1. Natural products as SIRT3 activators with multiple mechanisms

Natural products are rich sources of SIRT3 activators and offer significant potential for discovering drugs that enhance the negentropy capacity of the body [16]. These compounds typically activate SIRT3 through one or more mechanisms including upregulating its expression, increasing NAD+ levels, or directly binding to and allosterically activating the enzyme (Table 2).

4.1.1. Metformin

Metformin, a well-known clinical hypoglycemic drug, can activate SIRT3 and other members of the sirtuin family to treat metabolic, inflammatory, and age-related diseases. Metformin upregulates SIRT3 expression in skeletal muscle, promoting glucose uptake and ameliorating insulin resistance [102], and in cardiovascular models, where it confers protection against hypoxia/reoxygenation injury [103]. Metformin also counteracts oxidative stress and senescence by increasing mitochondrial SIRT3 levels [104] and reversing H2O2-induced osteoblast apoptosis [105]. Clinically, metformin attenuates leukocyte oxidative stress in T2DM patients by coordinating the upregulation of SIRT3 and glutathione peroxidase 1 expression [106]. Paradoxically, metformin can suppress SIRT3 expression in the liver via AMPK-independent mechanisms, reducing mitochondrial ATP production and increasing protein acetylation [166]. These contrasting findings highlight the tissue-specific and dose-dependent effects of metformin on SIRT3. Although metformin represents an indirect SIRT3 modulator with proven clinical benefits, such as in a clinical trial (NCT05949008, Phase 4) for the treatment of diabetes, its mechanistic relationship with SIRT3 requires further clarification because no direct binding or disease-dependent complexity has been confirmed.

4.1.2. Berberine

BBR is a natural isoquinoline alkaloid derived from traditional medicinal plants such as Coptis chinensis. BBR has been traditionally used in the clinic for its antimicrobial properties and, more recently, for the treatment of metabolic diseases. BBR acts through multiple mechanisms to treat metabolic diseases, including AMPK activation, modulation of the gut microbiota, and upregulation of low-density lipoprotein receptors (LDLRs) [167], [168]. The negentropic mechanism is considered the primary target of BBR, with SIRT3 serving as a key “head goose molecule” [16], [30]. In general, BBR activates SIRT3 through three pathways: ① Direct binding and activation. Our recent work revealed that BBR is a mitochondria-homing agent that directly binds to and activates SIRT3. This interaction triggers the selective and reversible dissociation of mitochondrial complex I and mediates the deacetylation of its NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), ultimately rectifying hepatocellular glucose and lipid metabolism [31]. ② Indirect pathways involving NAD+ and AMPK. BBR inhibits mitochondrial complex I, increasing the adenosine monophosphate-activated protein (AMP)/ATP ratio and activating AMPK. This activation upregulates nicotinamide phosphoribosyltransferase (NAMPT), increasing the level of intracellular NAD+, an essential cofactor for SIRT3 activation [107], [169]. ③ Upregulation of SIRT3 expression. BBR restores SIRT3 expression and activity in rodents fed a HFD, alleviating mitochondrial dysfunction and promoting fatty acid oxidation via the deacetylation of LCAD [107], [170]. BBR also inhibits MAPK/NF-κB signaling in adipose tissue through this mechanism [108].

Clinically, oral administration of BBR to patients with hypercholesterolemia for more than three months reduced the total cholesterol level by 29%, triglyceride level by 35%, and low-density lipoprotein cholesterol level by 25% [171]. In addition, similar to metformin and rosiglitazone, BBR is safe and effective for treating patients with T2DM because of its ability to lower blood glucose levels [172]. These pleiotropic effects, which also involve other targets, such as AMPK, LDLR, insulin receptor (InsR), eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2), and the gut microbiota (conceptualized as a “drug cloud” or dCloud) [16], [168], work in concert with SIRT3 activation to activate the negentropy capacity of the body, as indicated by the success of BBR ursodeoxycholate (HTD1801) in clinical trials for metabolic dysfunction-associated steatohepatitis (MASH) and T2DM [173], [174].

4.1.3. Silybin

Silybin, a flavonolignan from Silybum marianum, is recognized for its antioxidant and hepatoprotective properties [109] and has recently attracted renewed interest as a SIRT3 inducer [110]. In cisplatin-induced models of acute kidney injury, silybin increased Sirt3 messenger RNA (mRNA) and protein levels in the renal tissue of cisplatin-treated mice and human kidney 2 cells, restoring mitochondrial function and reducing oxidative damage [110]. In addition, the NAD+/SIRT2 pathway and AMPK/transforming growth factor beta 1 (TGF-β1)/Smad signaling are important mediators through which silybin inhibits NLRP3 inflammasome activation or improves glucose and lipid metabolism in rodent NAFLD models [175], [176]. A clinical trial (NCT03538327, Phase 4) is underway to investigate the metabolic and vascular effects of silybin in hypertensive patients.

4.1.4. Resveratrol (RSV)

RSV is a polyphenolic compound that activates the mitochondrial deacetylase SIRT3, as well as other sirtuin members, including SIRT1 and SIRT5, and thus plays crucial roles in antioxidant protection and metabolic regulation [33]. The mechanisms by which RSV activates SIRT3 are primarily indirect and involve the AMPK-PGC-1α-estrogen-related receptor alpha (ERRα) axis and an increase in the NAD+/NADH ratio [111], [112]. Notably, RSV can also exhibit inhibitory effects by directly interacting with the sirtuin catalytic core to suppress SIRT3-dependent deacetylation of GDH while stimulating SIRT5 [113], [114]. In addition to regulating SIRT3, RSV has been shown to activate various transcription factors and antioxidant enzymes and suppress antiapoptotic genes and inflammatory biomarkers in aging-related diseases [177]. Despite challenges such as promiscuous target engagement and extensive first-pass metabolism [33], a clinical trial (NCT04886297, Phase 3) is currently investigating its utility for lipid metabolism disorders.

4.1.5. Other natural products

Caffeine, recognized for its antioxidant properties, directly binds to and enhances SIRT3 activity, promoting SOD2 deacetylation and restoring its antioxidant capacity [115]. In addition, caffeine facilitates the conversion of ADP to ATP, which increases hepatic cyclic adenosine monophosphate (cAMP) levels and cAMP response binding protein (CREB) phosphorylation, potentially enhancing SIRT3 expression and downstream AMPK and ACC phosphorylation [116]. The upregulation of SIRT3 expression by caffeine may be crucial for alleviating high-energy diet-induced hepatic steatosis [116]. On the basis of this well-confirmed mechanism, a clinical trial (NCT02929901, Phase 3) evaluated the effects of supplementation with the main components of coffee (caffeine and chlorogenic acid) on inflammatory and metabolic factors, hepatic steatosis, and fibrosis in NAFLD patients with T2DM.

Melatonin, a mitochondrially synthesized indoleamine, has several bioactivities, including the regulation of circadian rhythms, antioxidant defense, and the maintenance of mitochondrial homeostasis through the activation of SIRT3 [178]. Melatonin coexists with SIRT3 in mitochondria [179] and modulates SIRT3 by enhancing its activity without affecting protein expression [180]. Melatonin also upregulates SIRT3 expression through upstream AMPK-PGC-1α-SIRT3 signaling pathways [181]. In addition, melatonin attenuates anoxia/reoxygenation injury by inhibiting excessive mitophagy through the melatonin membrane receptor 2 (MT2)/SIRT3/FoxO3a signaling pathway [117]. Supported by preclinical evidence of metabolic regulation and anti-inflammatory effects, a clinical trial (NCT02681887, Phase 3) for the treatment of diabetes is underway [118].

Dihydromyricetin (DHY), a flavonoid compound from Ampelopsis grossedentata, is recognized for its potential therapeutic effects on various metabolic disorders. DHY improves glucose and lipid metabolism, mitigates inflammatory responses, and reduces oxidative stress through several signaling pathways, including AMPK, mTOR/autophagy, PGC-1α/SIRT3, mitogen-activated protein kinase (MEK)/extracellular regulated protein kinases (ERK), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) [119], [120]. Notably, the increase in SIRT3 protein expression induced by DHY plays a pivotal therapeutic role in diabetic mice [121] and in mice fed a HFD [120], [122]. DHY also promotes the binding of activating protein-1 (AP-1), PGC-1α, or other factors to the SIRT3 promoter, thereby increasing SIRT3 expression and suppressing oxidative stress, inflammation, and necroptosis in mice with streptozotocin (STZ)-induced diabetes [123]. A clinical trial (NCT03606694, Phase 2) is registered in Mexico to investigate the effects of DHY on glycemic control, insulin sensitivity, and insulin secretion in individuals with T2DM.

Honokiol, a biphenolic lignan extracted from the traditional Chinese herb Magnolia bark (Hou Po), exhibits anti-inflammatory, antioxidant, antidepressant, neuroprotective, and anticancer properties [124], [125]. Its therapeutic potential in mitochondrial dysfunction-related metabolic disorders is attributed to the modulation of SIRT3, either through direct binding to SIRT3 [126] or indirect upregulation of SIRT3 expression via the AMPK/PGC-1α signaling pathway [127]. Despite limited clinical evidence, nanoparticle-based delivery systems improve the bioavailability and safety of honokiol, supporting its translational potential [182].

Oroxylin A, a bioactive flavonoid from Scutellaria baicalensis and Oroxylum indicum, has emerged as a potent SIRT3 activator with broad therapeutic effects in metabolic diseases and cancer [128], [129]. Mechanistically, oroxylin A indirectly increases the expression and/or activity of SIRT3, which subsequently deacetylates mitochondrial targets such as cypD to inhibit glycolysis [129]. Compared with other SIRT3 activators, such as RSV, oroxylin A exhibits superior mitochondrial specificity and metabolic stability, thereby minimizing off-target effects [183]. Despite promising preclinical efficacy [130], the clinical translation of oroxylin A has been limited to early-phase safety trials for acute liver injury [184]. Other compounds, such as sesamin (a known antioxidant from sesamin seeds), licoisoflavone A (a bioactive compound from Tongmaiyangxin Pills), and pyrroloquinoline quinone (PQQ; an aromatic heterocyclic anionic orthoquinone), can upregulate the protein expression of SIRT3 [65], [131], [132], [133], [134], [185]. Although these compounds show potential for the treatment of metabolic disorders, they are still in the early stages of development, and their long-term safety and clinical potential require further validation.

4.2. Synthetic compounds for direct binding and activation of SIRT3

SIRT3 is considered a “head goose molecule” that induces negentropy; therefore, researchers are striving to synthesize highly efficient, low-toxicity candidate compounds that directly target SIRT3 (Table 2).

2-Aminophenyl pyrazoloquinoline carboxamide (2-APQC) was developed as a potent and selective activator of SIRT3 on the basis of targeted molecular docking studies on pocket L [101]. The unique selectivity of 2-APQC for SIRT3 contributes to its therapeutic efficacy in both in vitro and in vivo models of isoproterenol-induced cardiac hypertrophy and myocardial fibrosis [101].

7-Hydroxy-3-(4′-methoxyphenyl) coumarin (C12), discovered in 2017, selectively activates SIRT3-mediated deacetylation of MnSOD, thereby enhancing the mitochondrial antioxidant capacity and metabolic function [113]. Structural studies have indicated that C12 has high binding affinity and specificity for SIRT3 [113]. In models of cardiac hypertrophy, the C12-derived analog SZC-6 reduces left ventricular dysfunction, enhances mitochondrial respiration, and decreases ROS through the SIRT3-LKB1-AMPK pathway [135]. C12 also rescues mitochondrial dysfunction in models of amyotrophic lateral sclerosis by reducing the number of acetylated lysine residues and improving neuronal survival [136].

ADTL-SA1215, a novel allosteric SIRT3 activator, was developed using structure-based drug discovery approaches. ADTL-SA1215 targets a hydrophobic allosteric pocket near the SIRT3 acyl-lysine binding site [137]. Mechanistic characterization revealed that ADTL-SA1215 achieves SIRT3 selectivity through unique molecular interactions that stabilize the allosteric site and increase the deacetylase activity of SIRT3 by approximately twofold in triple-negative breast cancer cells. This activation results in a concentration-dependent decrease in acetylation levels at lysines 68 and 122 of the canonical SIRT3 substrate manganese superoxide dismutase. Furthermore, in mouse xenograft models, ADTL-SA1215 induces autophagy by modulating autophagy-associated regulatory proteins, thereby alleviating triple-negative breast cancer [137], [138].

The 1,4-dihydropyridine scaffold was initially identified as a pan-sirtuin modulator [186]. The subsequent development of potent and selective next-generation SIRT3 activators was achieved through rational structural optimization guided by structure‒activity relationship analysis [139]. Among these, 1,4-dihydropyridine compound 31 (diethyl 4-phenyl-1-(3,4,5-trimethoxybenzoyl)-1,4-dihydropyridine-3,5-dicarboxylate) enhances the activity of GDH and increases the levels of deacetylated K68- and K122-acMnSOD in cancer cells, both of which are indicators of SIRT3 activation [139], [187], [188]. Although the current experimental data are limited to cellular models, specifically breast and thyroid cancer cell lines, the observed increase in metabolic enzyme activity in these models aligns with the established role of SIRT3 in metabolic diseases, as demonstrated in HFD and diabetic mouse models. These findings suggest its potential as a therapeutic target for metabolic disorders.

SKLB-11A was recently identified through a hybrid strategy combining computational, structural transformation, and experimental approaches. SKLB-11A was recognized as a breakthrough candidate with submicromolar affinity and high selectivity for SIRT3, offering a first-in-class small molecule as an allosteric SIRT3 activator [140], [141]. SKLB-11A binds to a unique allosteric site on SIRT3, distinct from the NAD+-binding domain, and triggers a conformational rearrangement that is critical for enzyme activation. In preclinical models, SKLB-11A showed robust cardioprotective effects and reduced myocardial ischemia/reperfusion injury [141].

4.3. NAD+ precursors for SIRT3 activation

NAD+ is a crucial cosubstrate for sirtuins, particularly SIRT1 and SIRT3, and plays a central role in regulating energy metabolism, oxidative stress, and aging [142], [189]. A unique reciprocal relationship exists between SIRT3 and NAD+ bioavailability [190]. SIRT3 removes the acetyl group from the substrate lysine by transferring ADP-ribose from NAD+ to the substrate, generating 2′-O-acyl-ADP-ribose and nicotinamide. In this mechanism, NAD+ does not interact directly with SIRT3 but does bind to its ADP-ribose to facilitate the deacetylation reactions of the SIRT3-substrate complex by altering the conformation of the substrate [115]. SIRT3 can bind to and deacetylate nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3), thereby increasing its enzymatic activity and increasing mitochondrial NAD+ production. This creates a positive feedback loop that further activates SIRT3, a mechanism demonstrated in the mitigation of cardiac hypertrophy [190].

Increasing intracellular NAD+ levels by increasing the supply of cell-permeable NAD+ precursors offers an alternative approach for activating sirtuins (Table 2). In addition to diet-derived and endogenous biosynthetic pathways, extrinsic approaches are effective at increasing the NAD+ pool in vivo. These methods include direct supplementation with NAD+ precursors such as nicotinamide mononucleotide (NMN), nicotinamide (NAM), and nicotinamide riboside (NR) to increase NAD+ levels and enhance SIRT3 activity. For example, NMN stimulates mitochondrial SIRT3, and its beneficial effects on mitochondrial deacetylation and cardioprotection are blunted in the hearts of Sirt3−/− mice [191]. Long-term NMN administration mitigates metabolic disturbances and physiological decline induced by a HFD in aging mice [143] and improves muscle insulin sensitivity, insulin signaling, and muscle remodeling in overweight or obese women with prediabetes [144]. Similarly, NAM restores NAD+ levels and improves diastolic function in rodent models of aging and hypertension [145], whereas NR enhances insulin sensitivity and reduces hepatic steatosis in models of obesity and type 2 diabetes [142]. Clinical observations corroborate these findings. High dietary intake of naturally occurring NAD+ precursors, such as NAM, correlated with lower blood pressure and a reduced risk of cardiac mortality in a long-term human cohort study [145]. Compared with low-dose (5 mg·kg-1) and high-dose (900 mg·kg-1) NR, NR at a controlled dosage of 30 mg·kg-1 body weight yields better beneficial effects and improved metabolic adaptability [146]. However, dosage and genetic background may influence the experimental phenotypes and should be considered in application [189].

Although the activation of SIRT3 shows promise for treating metabolic diseases, its inhibition represents a viable therapeutic strategy for other conditions, particularly in oncology. For example, 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP), the first reported selective SIRT3 inhibitor, has been shown to reduce intracellular ATP levels and increase superoxide production. In cardiac models, 3-TYP antagonizes the activating effect of melatonin on SIRT3, decreases SOD2 deacetylation, and impairs its cardioprotective effects. Although 3-TYP exhibits more potent inhibitory activity against SIRT3 than against SIRT1 and SIRT2, its structure is based on a nicotinamide analog, which poses potential off-target risks [55]. Another inhibitor, LC0296, occupies the NAD+ binding pocket and disrupts the catalytic cycles of enzymes, potentially inducing apoptosis and inhibiting proliferation in cancer cells [192]. Similarly, the SIRT3 inhibitor 2-methoxyestradiol, a natural derivative of 17β-estradiol that binds to both canonical and allosteric sites, has been shown to inhibit mitochondrial biogenesis in an osteosarcoma cancer cell model [193]. These studies underscore the potential of SIRT3 inhibition as a strategy to reduce cancer cell survival. Notably, however, SIRT3 may play distinct roles across various cancer types, and its dual effects should be carefully considered [55].

5. Conclusions and future perspectives

The multifactorial nature of metabolic diseases such as diabetes, obesity, and hepatic steatosis necessitates therapeutic strategies that address systemic pathogenic disruptions [194], [195], which we conceptualize as an “increase in biological entropy.” Given its central role in regulating glucose/lipid metabolism, mitochondrial energy balance, oxidative stress, and inflammation, we propose that SIRT3 functions as a “head goose molecule.” By guiding the realignment of dysregulated metabolic and inflammatory networks, SIRT3 activation promotes a negentropic mechanism essential for the long-term management of these chronic conditions. Activators of SIRT3, including natural products, synthetic compounds, and NAD+ supplements, represent mild, safe, and sustainable therapeutic modalities. Although substantial preclinical evidence supports the metabolic and tissue-protective effects of SIRT3 activation, translational success depends on overcoming challenges related to compound selectivity, delivery, tissue/organ specificity, and long-term safety. Addressing these hurdles will enable SIRT3 activators to emerge as innovative therapeutics for non-tumor-related metabolic diseases. In conclusion, the regulatory framework, with SIRT3 as the “head goose molecule” that activates the negentropy capacity of the body, can serve as a practical reference for drug repurposing research and treatment strategy selection. We anticipate further practical applications of this framework following future large-scale multicenter clinical trials.

References

Publishing order | Descend order by publishing year | Descend order by cited within
[1]

Neeland IJ, Lim S, Tchernof A, Gastaldelli A, Rangaswami J, Ndumele CE, et al. Metabolic syndrome. Nat Rev Dis Primers 2024; 10(1):77.
[2]

Byrne CD, Targher G. MASLD, MAFLD, or NAFLD criteria: have we re-created the confusion and acrimony surrounding metabolic syndrome? M&TOD 2024; 4(2):10.
[3]

Chew NWS, Ng CH, Tan DJH, Kong G, Lin C, Chin YH, et al. The global burden of metabolic disease: data from 2000 to 2019. Cell Metab 2023; 35(3):414.
[4]

Wong RJ. Epidemiology of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD). M&TOD 2024; 4(4):35.
[5]

Liu H, Wang S, Wang J, Guo X, Song Y, Fu K, et al. Energy metabolism in health and diseases. Signal Transduct Target Ther 2025; 10(1):69.
[6]

Mlynarska E, Czarnik W, Dzieza N, Jedraszak W, Majchrowicz G, Prusinowski F, et al. Type 2 diabetes mellitus: new pathogenetic mechanisms, treatment and the most important complications. Int J Mol Sci 2025; 26(3):1094.
[7]

Liu Z, Zhang Y, Graham S, Wang X, Cai D, Huang M, et al. Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. J Hepatol 2020; 73(2):263-76.
[8]

Mitten EK, Baffy G. Mechanobiology in the development and progression of nonalcoholic fatty liver disease: an updated review. Metab Target Organ Damage 2023; 3(1):2.
[9]

Cruz-Cruz I, Bernate-Obando G, Larque C, Escalona R, Pinto-Almazan R, Velasco M. Early effects of metabolic syndrome on ATP-sensitive potassium channels from rat pancreatic beta cells. Metabolites 2022; 12(4):365.
[10]

Dong XC, Chowdhury K, Huang M, Kim HG. Signal transduction and molecular regulation in fatty liver disease. Antioxid Redox Signal 2021; 35(9):689-717.
[11]

Visuthranukul C, Kwanbunbumpen T, Chongpison Y, Chamni S, Panichsillaphakit E, Uaariyapanichkul J, et al. The impact of dietary fiber as a prebiotic on inflammation in children with obesity. Foods 2022; 11(18):2856.
[12]

Harshfield EL, Fauman EB, Stacey D, Paul DS, Ziemek D, Ong RMY, et al. Genome-wide analysis of blood lipid metabolites in over 5000 south Asians reveals biological insights at cardiometabolic disease loci. BMC Med 2021; 19(1):232.
[13]

Huang Z, Sun A. Metabolism, inflammation, and cardiovascular diseases from basic research to clinical practice. Cardiol Plus 2023; 8(1):4-5.
[14]

Wang Z. The entropy perspective on human illness and aging. Engineering 2022; 9(2):22-6.
[15]

Guo HH, Shen HR, Wang LL, Luo ZG, Zhang JL, Zhang HJ, et al. Berberine is a potential alternative for metformin with good regulatory effect on lipids in treating metabolic diseases. Biomed Pharmacother 2023; 163:114754.
[16]

Gao TL, Guo HH, Jiang JD. Neg-entropy mechanism as a target for natural medicines. Engineering 2024; 38(7):11-2.
[17]

Guo HH, Gao TL, Ma XL, Tie C, Jiang JD. Application of bio-entropy in drug evaluation. Chin Pharm J 2025; 60(3):209-13. Chinese.
[18]

Lin YH, Liao YY, Yeh CK, Yang KC, Tsui PH. Ultrasound entropy imaging of nonalcoholic fatty liver disease: association with metabolic syndrome. Entropy 2018; 20(12):893.
[19]

Breslavets A, Breslavets M, Shear NH. Quantification of randomness (entropy) as a clinical tool to assess the severity of skin disease. Med Hypotheses 2019; 132:109311.
[20]

Kalloo J, Priscilla S, Puttanna A. Pharmacological management of type 2 diabetes: clinical considerations and future perspectives. M&TOD 2023; 3(2):7.
[21]

Chandrasekaran P, Weiskirchen R. Diabetes mellitus and heart disease. M&TOD 2024; 4(2):18.
[22]

Clemente-Suarez VJ, Martin-Rodriguez A, Redondo-Florez L, Lopez-Mora C, Yanez-Sepulveda R, Tornero-Aguilera JF. New insights and potential therapeutic interventions in metabolic diseases. Int J Mol Sci 2023; 24(13):10672.
[23]

Guerra JVS, Dias MMG, Brilhante A, Terra MF, Garcia-Arevalo M, Figueira ACM. Multifactorial basis and therapeutic strategies in metabolism-related diseases. Nutrients 2021; 13(8):2830.
[24]

Jiang J, Li H, Tang M, Lei L, Li HY, Dong B, et al. Upregulation of hepatic glutathione S-transferase alpha 1 ameliorates metabolic dysfunction-associated steatosis by degrading fatty acid binding protein 1. Int J Mol Sci 2024; 25(10):5086.
[25]

Ma X, Feng D, Lu Y, Sun N, Wang J, Xu L. Editorial: novel strategies targeting obesity and metabolic diseases, volume II. Front Physiol 2024; 15:1342943.
[26]

Pinheiro MM, Pinheiro FMM, Garo ML, Pastore D, Pacifici F, Ricordi C, et al. Prevention and treatment of type 1 diabetes: in search of the ideal combination therapy targeting multiple immunometabolic pathways. M&TOD 2024; 4(3):19.
[27]

Li H, Liu NN, Li JR, Dong B, Wang MX, Tan JL, et al. Combined use of bicyclol and berberine alleviates mouse nonalcoholic fatty liver disease. Front Pharmacol 2022; 13:843872.
[28]

Li H, Liu NN, Peng ZG. Effect of bicyclol on blood biomarkers of NAFLD: a systematic review and meta-analysis. BMJ Open 2020; 10(12):e039700.
[29]

Zhu JY, Tang M, Li H, Shi YL, Li YM, Li YH, et al. Design, synthesis and triglyceride-lowering activity of tricyclic matrine derivatives for the intervention of non-alcoholic fatty liver disease. Bioorg Chem 2024; 142:106925.
[30]

Li R, Ren G, Han YX, Wang LL, Jiang JD. Searching for head goose molecules as drug target. Chin Med Biotechnol 2024; 19(6):489-92. Chinese.
[31]

Wang X, Li H, Li J, Lei L, Xu J, Sun H, et al. Berberine dissociates mitochondrial complex I by SIRT3-dependent deacetylation of NDUFS1 to improve hepatocellular glucose and lipid metabolism. Sci China Life Sci 2025; 68(9):2676-96.
[32]

Ning Y, Dou X, Wang Z, Shi K, Wang Z, Ding C, et al. SIRT3: a potential therapeutic target for liver fibrosis. Pharmacol Ther 2024; 257:108639.
[33]

Wang Y, He J, Liao M, Hu M, Li W, Ouyang H, et al. An overview of sirtuins as potential therapeutic target: structure, function and modulators. Eur J Med Chem 2019; 161:16148-77.
[34]

Wu QJ, Zhang TN, Chen HH, Yu XF, Lv JL, Liu YY, et al. The sirtuin family in health and disease. Signal Transduct Target Ther 2022; 7(1):402.
[35]

Tao L, Zhou Y, Luo Y, Qiu J, Xiao Y, Zou J, et al. Epigenetic regulation in cancer therapy: from mechanisms to clinical advances. MedComm Oncol 2024; 3(1):e59.
[36]

Erion DM, Yonemitsu S, Nie Y, Nagai Y, Gillum MP, Hsiao JJ, et al. Sirt1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats. Proc Natl Acad Sci USA 2009; 106(27):11288-93.
[37]

Cornejo PJ, Vergoni B, Ohanna M, Angot B, Gonzalez T, Jager J, et al. The stress-responsive microRNA-34a alters insulin signaling and actions in adipocytes through induction of the tyrosine phosphatase PTP1B. Cells 2022; 11(16):2581.
[38]

Watanabe H, Inaba Y, Kimura K, Matsumoto M, Kaneko S, Kasuga M, et al. SIRT2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein. Nat Commun 2018; 9(1):30.
[39]

Betsinger CN, Cristea IM. Mitochondrial function, metabolic regulation, and human disease viewed through the prism of sirtuin 4 (SIRT4) functions. J Proteome Res 2019; 18(5):1929-38.
[40]

Han Y, Zhou S, Coetzee S, Chen A. SIRT4 and its roles in energy and redox metabolism in health, disease and during exercise. Front Physiol 2019; 10:1006.
[41]

Ma Y, Fei X. SIRT 5 regulates pancreatic beta-cell proliferation and insulin secretion in type 2 diabetes. Exp Ther Med 2018; 16(2):1417-25.
[42]

Yamagata K, Mizumoto T, Yoshizawa T. The emerging role of SIRT7 in glucose and lipid metabolism. Cells 2023; 13(1):48.
[43]

Li H, Xu M, Lee J, He C, Xie Z. Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice. Am J Physiol Endocrinol Metab 2012; 303(10):E1234-44.
[44]

Li S, Guo L. The role of sirtuin 2 in liver—an extensive and complex biological process. Life Sci 2024; 339:122431.
[45]

Zhang T, Liu J, Tong Q, Lin L. SIRT 3 acts as a positive autophagy regulator to promote lipid mobilization in adipocytes via activating AMPK. Int J Mol Sci 2020; 21(2):372.
[46]

Nasrin N, Wu X, Fortier E, Feng Y, Bare OC, Chen S, et al. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 2010; 285(42):31995-2002.
[47]

Laurent G, de Boer VC, Finley LW, Sweeney M, Lu H, Schug TT, et al. SIRT4 represses peroxisome proliferator-activated receptor alpha activity to suppress hepatic fat oxidation. Mol Cell Biol 2013; 33(22):4552-61.
[48]

Wang CH, Wei YH. Roles of mitochondrial sirtuins in mitochondrial function, redox homeostasis, insulin resistance and type 2 diabetes. Int J Mol Sci 2020; 21(15):5266.
[49]

Fabbrizi E, Fiorentino F, Carafa V, Altucci L, Mai A, Rotili D. Emerging roles of SIRT5 in metabolism, cancer, and SARS-CoV-2 infection. Cells 2023; 12(6):852.
[50]

Du Y, Hu H, Qu S, Wang J, Hua C, Zhang J, et al. SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice. EBioMedicine 2018; 36:347-57.
[51]

Choubey SK, Prabhu D, Nachiappan M, Biswal J, Jeyakanthan J. Molecular modeling, dynamics studies and density functional theory approaches to identify potential inhibitors of SIRT4 protein from Homo sapiens: a novel target for the treatment of type 2 diabetes. J Biomol Struct Dyn 2017; 35(15):3316-29.
[52]

Tang Q, Liu Q, Yang X, Wu T, Huang C, Zhang J, et al. Sirtuin 6 supra-physiological overexpression in hypothalamic pro-opiomelanocortin neurons promotes obesity via the hypothalamus—adipose axis. FASEB J 2021; 35(3):e21408.
[53]

Raj S, Dsouza LA, Singh SP, Kanwal A. SIRT 6 deacetylase: a potential key regulator in the prevention of obesity, diabetes and neurodegenerative disease. Front Pharmacol 2020; 11:598326.
[54]

Chalkiadaki A, Guarente L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer 2015; 15(10):608-24.
[55]

Ouyang S, Zhang Q, Lou L, Zhu K, Li Z, Liu P, et al. The double-edged sword of SIRT3 in cancer and its therapeutic applications. Front Pharmacol 2022; 13:871560.
[56]

Zhong X, Huang M, Kim HG, Zhang Y, Chowdhury K, Cai W, et al. SIRT 6 protects against liver fibrosis by deacetylation and suppression of Smad3 in hepatic stellate cells. Cell Mol Gastroenterol Hepatol 2020; 10(2):341-64.
[57]

Zhu C, Huang M, Kim HG, Chowdhury K, Gao J, Liu S, et al. SIRT6 controls hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1. Biochim Biophys Acta Mol Basis Dis 2021; 1867(12):166249.
[58]

Arora A, Dey CS. SIRT 2 regulates insulin sensitivity in insulin resistant neuronal cells. Biochem Biophys Res Commun 2016; 474(4):747-52.
[59]

Yang W, Nagasawa K, Munch C, Xu Y, Satterstrom K, Jeong S, et al. Mitochondrial sirtuin network reveals dynamic SIRT3-dependent deacetylation in response to membrane depolarization. Cell 2016; 167(4):985-1000.e21.
[60]

Zhang J, Xiang H, Liu J, Chen Y, He RR, Liu B. Mitochondrial sirtuin 3: new emerging biological function and therapeutic target. Theranostics 2020; 10(18):8315-42.
[61]

Murugasamy K, Munjal A, Sundaresan NR. Emerging roles of SIRT3 in cardiac metabolism. Front Cardiovasc Med 2022; 9:850340.
[62]

Zhao Y, Li J, Ma A, Wang Z, Ni Y, Wu D, et al. Irisin alleviates hepatic steatosis by activating the autophagic SIRT 3 pathway. Chin Med J 2025; 10:1097.
[63]

Lantier L, Williams AS, Williams IM, Yang KK, Bracy DP, Goelzer M, et al. SIRT3 is crucial for maintaining skeletal muscle insulin action and protects against severe insulin resistance in high-fat-fed mice. Diabetes 2015; 64(9):3081-92.
[64]

Yu J, Auwerx J. The role of sirtuins in the control of metabolic homeostasis. Ann N Y Acad Sci 2009;1173:E10-9.
[65]

Lambona C, Zwergel C, Valente S, Mai A. SIRT 3 activation a promise in drug development? New insights into SIRT3 biology and its implications on the drug discovery process. J Med Chem 2024; 67(3):1662-89.
[66]

Jing E, Emanuelli B, Hirschey MD, Boucher J, Lee KY, Lombard D, et al. Sirtuin-3 (SIRT3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc Natl Acad Sci USA 2011; 108(35):14608-13.
[67]

Jing E, O’Neill BT, Rardin MJ, Kleinridders A, Ilkeyeva OR, Ussar S, et al. SIRT3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation. Diabetes 2013; 62(10):3404-17.
[68]

Zhang Y, Wen P, Luo J, Ding H, Cao H, He W, et al. Sirtuin 3 regulates mitochondrial protein acetylation and metabolism in tubular epithelial cells during renal fibrosis. Cell Death Dis 2021; 12(9):847.
[69]

Zhang Q, Siyuan Z, Xing C, Ruxiu L. SIRT 3 regulates mitochondrial function: a promising star target for cardiovascular disease therapy. Biomed Pharmacother 2024; 170:116004.
[70]

Carnevale I, Pellegrini L, D’Aquila P, Saladini S, Lococo E, Polletta L, et al. SIRT1-SIRT3 axis regulates cellular response to oxidative stress and etoposide. J Cell Physiol 2017; 232(7):1835-44.
[71]

Shen H, Qi X, Hu Y, Wang Y, Zhang J, Liu Z, et al. Targeting sirtuins for cancer therapy: epigenetics modifications and beyond. Theranostics 2024; 14(17):6726-67.
[72]

Xiong Y, Wang L, Wang S, Wang M, Zhao J, Zhang Z, et al. SIRT 3 deacetylates and promotes degradation of P53 in PTEN-defective non-small cell lung cancer. J Cancer Res Clin Oncol 2018; 144(2):189-98.
[73]

Wang S, Zhang J, Deng X, Zhao Y, Xu K. Advances in characterization of SIRT3 deacetylation targets in mitochondrial function. Biochimie 2020; 179:1-13.
[74]

Rui L. Energy metabolism in the liver. Compr Physiol 2014; 4(1):177-97.
[75]

Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, et al. SIRT. deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 2010; 12(6):654-61.
[76]

Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, et al. A role for the mitochondrial deacetylase Sirt 3 in regulating energy homeostasis. Proc Natl Acad Sci USA 2008; 105(38):14447-52.
[77]

Nassir F, Arndt JJ, Johnson SA, Ibdah JA. Regulation of mitochondrial trifunctional protein modulates nonalcoholic fatty liver disease in mice. J Lipid Res 2018; 59(6):967-73.
[78]

Zhang Y, Bharathi SS, Rardin MJ, Uppala R, Verdin E, Gibson BW, et al. SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long-chain acyl-CoA dehydrogenase. PLoS One 2015; 10(3):e0122297.
[79]

Lu Z, Chen Y, Aponte AM, Battaglia V, Gucek M, Sack MN. Prolonged fasting identifies heat shock protein 10 as a sirtuin 3 substrate: elucidating a new mechanism linking mitochondrial protein acetylation to fatty acid oxidation enzyme folding and function. J Biol Chem 2015; 290(4):2466-76.
[80]

Pham DV, Tilija Pun N, Park PH. Autophagy activation and SREBP-1 induction contribute to fatty acid metabolic reprogramming by leptin in breast cancer cells. Mol Oncol 2021; 15(2):657-78.
[81]

Li M, Li D, Wang HY, Zhang W, Zhuo Z, Guo H, et al. Leptin decreases Th17/Treg ratio to facilitate neuroblastoma via inhibiting long-chain fatty acid catabolism in tumor cells. OncoImmunology 2025; 14(1):2460281.
[82]

Hopkins TA, Dyck JR, Lopaschuk GD. AMP-activated protein kinase regulation of fatty acid oxidation in the ischaemic heart. Biochem Soc Trans 2003; 31(Pt 1):207-12.
[83]

Zhang YK, Qu YY, Lin Y, Wu XH, Chen HZ, Wang X, et al. Enoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients. Nat Commun 2017; 8(1):464.
[84]

Pillai VB, Sundaresan NR, Kim G, Gupta M, Rajamohan SB, Pillai JB, et al. Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J Biol Chem 2010; 285(5):3133-44.
[85]

Zhang HH, Ma XJ, Wu LN, Zhao YY, Zhang PY, Zhang YH, et al. SIRT1 attenuates high glucose-induced insulin resistance via reducing mitochondrial dysfunction in skeletal muscle cells. Exp Biol Med 2015; 240(5):557-65.
[86]

Yang Y, Cimen H, Han MJ, Shi T, Deng JH, Koc H, et al. NAD+-dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of the ribosomal protein MRPL10. J Biol Chem 2010; 285(10):7417-29.
[87]

Wang Y, Zhang X, Wang P, Shen Y, Yuan K, Li M, et al. SIRT3 overexpression alleviates hyperglycemia-induced vascular inflammation through regulating redox balance, cell survival, and AMPK-mediated mitochondrial homeostasis. J Recept Signal Transduct Res 2019; 39(4):341-9.
[88]

Shen Y, Wu Q, Shi J, Zhou S. Regulation of SIRT3 on mitochondrial functions and oxidative stress in Parkinson’s disease. Biomed Pharmacother 2020; 132:110928.
[89]

Samant SA, Zhang HJ, Hong Z, Pillai VB, Sundaresan NR, Wolfgeher D, et al. SIRT 3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol 2014; 34(5):807-19.
[90]

Shen Y, Wang X, Nan N, Fu X, Zeng R, Yang Y, et al. SIRT3-mediated deacetylation of SDHA rescues mitochondrial bioenergetics contributing to neuroprotection in rotenone-induced PD models. Mol Neurobiol 2024; 61(7):4402-20.
[91]

Meng H, Yan WY, Lei YH, Wan Z, Hou YY, Sun LK, et al. SIRT3 regulation of mitochondrial quality control in neurodegenerative diseases. Front Aging Neurosci 2019; 11:313.
[92]

Tseng AH, Shieh SS, Wang DL. SIRT 3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med 2013; 63:63222-34.
[93]

Ansari A, Rahman MS, Saha SK, Saikot FK, Deep A, Kim KH. Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell 2017; 16(1):4-16.
[94]

Zhao WY, Zhang L, Sui MX, Zhu YH, Zeng L. Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury. Sci Rep 2016; 6(1):33201.
[95]

Guo X, Yan F, Li J, Zhang C, Su H, Bu P. SIRT 3 ablation deteriorates obesity-related cardiac remodeling by modulating ROS-NF-kappaB-MCP-1 signaling pathway. J Cardiovasc Pharmacol 2020; 76(3):296-304.
[96]

Stuart JA, Aibueku O, Bagshaw O, Moradi F. Hypoxia inducible factors as mediators of reactive oxygen/nitrogen species homeostasis in physiological normoxia. Med Hypotheses 2019; 129:109249.
[97]

Liu P, Huang G, Wei T, Gao J, Huang C, Sun M, et al. Sirtuin 3-induced macrophage autophagy in regulating NLRP 3 inflammasome activation. Biochim Biophys Acta Mol Basis Dis 2018; 1864(3):764-77.
[98]

Cao M, Zhao Q, Sun X, Qian H, Lyu S, Chen R, et al. Sirtuin 3: emerging therapeutic target for cardiovascular diseases. Free Radic Biol Med 2022; 180:63-74.
[99]

Lu T, Ding L, Zheng X, Li Y, Wei W, Liu W, et al. Alisol a exerts neuroprotective effects against HFD-induced pathological brain aging via the SIRT3-NF-kappaB/MAPK pathway. Mol Neurobiol 2024; 61(2):753-71.
[100]

Koyama T, Kume S, Koya D, Araki S, Isshiki K, Chin-Kanasaki M, et al. SIRT3 attenuates palmitate-induced ROS production and inflammation in proximal tubular cells. Free Radic Biol Med 2011; 51(6):1258-67.
[101]

Peng F, Liao M, Jin W, Liu W, Li Z, Fan Z, et al. 2-APQC, a small-molecule activator of sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis. Signal Transduct Target Ther 2024; 9(1):133.
[102]

Song Y, Shi J, Wu Y, Han C, Zou J, Shi Y, et al. Metformin ameliorates insulin resistance in L6 rat skeletal muscle cells through upregulation of SIRT3. Chin Med J 2014; 127(8):1523-9.
[103]

Du Y, Zhang J, Fang F, Wei X, Zhang H, Tan H, et al. Metformin ameliorates hypoxia/reoxygenation-induced cardiomyocyte apoptosis based on the SIRT3 signaling pathway. Gene 2017; 626:182-8.
[104]

Hu D, Xie F, Xiao Y, Lu C, Zhong J, Huang D, et al. Metformin: a potential candidate for targeting aging mechanisms. Aging Dis 2021; 12(2):480-93.
[105]

Yang K, Pei L, Zhou S, Tao L, Zhu Y. Metformin attenuates H2O2-induced osteoblast apoptosis by regulating SIRT3 via the PI3K/AKT pathway. Exp Ther Med 2021; 22(5):1316.
[106]

Diaz-Morales N, Rovira-Llopis S, Banuls C, Lopez-Domenech S, Escribano-Lopez I, Veses S, et al. Does metformin protect diabetic patients from oxidative stress and leukocyte—endothelium interactions? Antioxid Redox Signal 2017; 27(17):1439-45.
[107]

Xu X, Zhu XP, Bai JY, Xia P, Li Y, Lu Y, et al. Berberine alleviates nonalcoholic fatty liver induced by a high-fat diet in mice by activating SIRT3. FASEB J 2019; 33(6):7289-300.
[108]

Li D, Yang C, Zhu JZ, Lopez E, Zhang T, Tong Q, et al. Berberine remodels adipose tissue to attenuate metabolic disorders by activating sirtuin 3. Acta Pharmacol Sin 2022; 43(5):1285-98.
[109]

Bijak M. Silybin, a major bioactive component of milk thistle (Silybum marianum l. gaernt.)—chemistry, bioavailability, and metabolism. Molecules 2017; 22(11):1942.
[110]

Li Y, Ye Z, Lai W, Rao J, Huang W, Zhang X, et al. Activation of sirtuin 3 by silybin attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury. Front Pharmacol 2017; 8:178.
[111]

Zhou X, Chen M, Zeng X, Yang J, Deng H, Yi L, et al. Resveratrol regulates mitochondrial reactive oxygen species homeostasis through SIRT3 signaling pathway in human vascular endothelial cells. Cell Death Dis 2014; 5(12):e1576.
[112]

Desquiret-Dumas V, Gueguen N, Leman G, Baron S, Nivet-Antoine V, Chupin S, et al. Resveratrol induces a mitochondrial complex I-dependent increase in NADH oxidation responsible for sirtuin activation in liver cells. J Biol Chem 2013; 288(51):36662-75.
[113]

Lu J, Zhang H, Chen X, Zou Y, Li J, Wang L, et al. A small molecule activator of SIRT3 promotes deacetylation and activation of manganese superoxide dismutase. Free Radic Biol Med 2017; 112:287-97.
[114]

Gertz M, Nguyen GT, Fischer F, Suenkel B, Schlicker C, Franzel B, et al. A molecular mechanism for direct sirtuin activation by resveratrol. PLoS One 2012; 7(11):e49761.
[115]

Xu H, Gan C, Gao Z, Huang Y, Wu S, Zhang D, et al. Caffeine targets SIRT 3 to enhance SOD2 activity in mitochondria. Front Cell Dev Biol 2020; 8:822.
[116]

Zhang SJ, Li YF, Wang GE, Tan RR, Tsoi B, Mao GW, et al. Caffeine ameliorates high energy diet-induced hepatic steatosis: sirtuin 3 acts as a bridge in the lipid metabolism pathway. Food Funct 2015; 6(8):2578-87.
[117]

Wu J, Yang Y, Gao Y, Wang Z, Ma J. Melatonin attenuates anoxia/reoxygenation injury by inhibiting excessive mitophagy through the MT2/SIRT3/FOXO3a signaling pathway in H9c2 cells. Drug Des Devel Ther 2020; 14:2047-60.
[118]

Akbari M, Ostadmohammadi V, Tabrizi R, Lankarani KB, Heydari ST, Amirani E, et al. The effects of melatonin supplementation on inflammatory markers among patients with metabolic syndrome or related disorders: a systematic review and meta-analysis of randomized controlled trials. Inflammopharmacology 2018; 26(4):899-907.
[119]

Wang Z, Cao Z, Yue Z, Yang Z. Research progress of dihydromyricetin in the treatment of diabetes mellitus. Front Endocrinol 2023; 14:1216907.
[120]

Zhou J, Yue J, Yao Y, Hou P, Zhang T, Zhang Q, et al. Dihydromyricetin protects intestinal barrier integrity by promoting IL-22 expression in ILC3s through the AMPK/SIRT3/STAT3 signaling pathway. Nutrients 2023; 15(2):355.
[121]

Hua YY, Zhang Y, Gong WW, Ding Y, Shen JR, Li H, et al. Dihydromyricetin improves endothelial dysfunction in diabetic mice via oxidative stress inhibition in a SIRT3-dependent manner. Int J Mol Sci 2020; 21(18):6699.
[122]

Zhou J, Hou P, Yao Y, Yue J, Zhang Q, Yi L, et al. Dihydromyricetin improves high-fat diet-induced hyperglycemia through ILC3 activation via a SIRT3-dependent mechanism. Mol Nutr Food Res 2022; 66(16):e2101093.
[123]

Chen Y, Zheng Y, Chen R, Shen J, Zhang S, Gu Y, et al. Dihydromyricetin attenuates diabetic cardiomyopathy by inhibiting oxidative stress, inflammation and necroptosis via sirtuin 3 activation. Antioxidants 2023; 12(1):200.
[124]

Sun J, Fu X, Liu Y, Wang Y, Huo B, Guo Y, et al. Hypoglycemic effect and mechanism of honokiol on type 2 diabetic mice. Drug Des Devel Ther 2015; 9:6327-42.
[125]

Pillai VB, Kanwal A, Fang YH, Sharp WW, Samant S, Arbiser J, et al. Honokiol, an activator of sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice. Oncotarget 2017; 8(21):34082-98.
[126]

Pillai VB, Samant S, Sundaresan NR, Raghuraman H, Kim G, Bonner MY, et al. Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial SIRT3. Nat Commun 2015; 6(1):6656.
[127]

Wang J, Nisar M, Huang C, Pan X, Lin D, Zheng G, et al. Small molecule natural compound agonist of SIRT3 as a therapeutic target for the treatment of intervertebral disc degeneration. Exp Mol Med 2018; 50(11):1-14.
[128]

Zhao K, Zhou Y, Qiao C, Ni T, Li Z, Wang X, et al. Oroxylin A promotes PTEN-mediated negative regulation of MDM2 transcription via SIRT3-mediated deacetylation to stabilize p53 and inhibit glycolysis in WT-p53 cancer cells. J Hematol Oncol 2015; 8(1):41.
[129]

Wei L, Zhou Y, Dai Q, Qiao C, Zhao L, Hui H, et al. Oroxylin A induces dissociation of hexokinase II from the mitochondria and inhibits glycolysis by SIRT3-mediated deacetylation of cyclophilin D in breast carcinoma. Cell Death Dis 2013; 4(4):e601.
[130]

Cai T, Xu X, Dong L, Liang S, Xin M, Wang T, et al. Oroxin A from Oroxylum indicum improves disordered lipid metabolism by inhibiting SREBPs in oleic acid-induced HepG2 cells and high-fat diet-fed non-insulin-resistant rats. Heliyon 2024; 10(7):e29168.
[131]

Fan D, Yang Z, Liu FY, Jin YG, Zhang N, Ni J, et al. Sesamin protects against cardiac remodeling via SIRT3/ROS pathway. Cell Physiol Biochem 2017; 44(6):2212-27.
[132]

Guo R, Liu N, Liu H, Zhang J, Zhang H, Wang Y, et al. High content screening identifies licoisoflavone A as a bioactive compound of Tongmaiyangxin Pills to restrain cardiomyocyte hypertrophy via activating SIRT3. Phytomedicine 2020; 68:153171.
[133]

Wang Z, Li Y, Wang Y, Zhao K, Chi Y, Wang B. Pyrroloquinoline quinine protects HK-2 cells against high glucose-induced oxidative stress and apoptosis through Sirt3 and PI3K/Akt/FOXO3a signaling pathway. Biochem Biophys Res Commun 2019; 508(2):398-404.
[134]

Wang X, Deng Q, Hou J, Pasunooti KK, Bermea K, Li K, et al. Editorial: design of novel inhibitors for ischemia/reperfusion injury targeting ferroptosis. Front Pharmacol 2024; 15:1475526.
[135]

Li ZY, Lu GQ, Lu J, Wang PX, Zhang XL, Zou Y, et al. SZC-6, a small-molecule activator of SIRT3, attenuates cardiac hypertrophy in mice. Acta Pharmacol Sin 2023; 44(3):546-60.
[136]

Hor JH, Santosa MM, Lim VJW, Ho BX, Taylor A, Khong ZJ, et al. ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT 3 activation. Cell Death Differ 2021; 28(4):1379-97.
[137]

Zhang J, Zou L, Shi D, Liu J, Zhang J, Zhao R, et al. Structure-guided design of a small-molecule activator of sirtuin-3 that modulates autophagy in triple negative breast cancer. J Med Chem 2021; 64(19):14192-216.
[138]

Bursch KL, Goetz CJ, Smith BC. Current trends in sirtuin activator and inhibitor development. Molecules 2024; 29(5):1185.
[139]

Suenkel B, Valente S, Zwergel C, Weiss S, Di Bello E, Fioravanti R, et al. Potent and specific activators for mitochondrial sirtuins SIRT3 and SIRT5. J Med Chem 2022; 65(20):14015-31.
[140]

Bi T, Cui Y, Liu S, Yu H, Qiu W, Hou KQ, et al. Ligand-enabled Pd-catalyzed sp3 C-H macrocyclization: synthesis and evaluation of macrocyclic sulfonamide for the treatment of Parkinson’s disease. Angew Chem Int Ed 2024; 63(45):e202412296.
[141]

Zhang D, Zhang J, Wu C, Xiao Y, Ji L, Hu J, et al. Unraveling small molecule-mediated sirtuin 3 activation at a distinct binding site for cardioprotective therapies. ACS Cent Sci 2025; 11(5):704-18.
[142]

Dollerup OL, Christensen B, Svart M, Schmidt MS, Sulek K, Ringgaard S, et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am J Clin Nutr 2018; 108(2):343-53.
[143]

Zhou AJ, Xiong ZE, Wang L, Chen XX, Wang ZP, Zhang YD, et al. Long-term administration of nicotinamide mononucleotide mitigates high-fat-diet-induced physiological decline in aging mice. J Nutr 2025; 155(1):237-49.
[144]

Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 2021; 372(6547):1224-9.
[145]

Abdellatif M, Trummer-Herbst V, Koser F, Durand S, Adao R, Vasques-Novoa F, et al. Nicotinamide for the treatment of heart failure with preserved ejection fraction. Sci Transl Med 2021; 13(580):eabd7064.
[146]

Shi W, Hegeman MA, van Dartel DAM, Tang J, Suarez M, Swarts H, et al. Effects of a wide range of dietary nicotinamide riboside (NR) concentrations on metabolic flexibility and white adipose tissue (WAT) of mice fed a mildly obesogenic diet. Mol Nutr Food Res 2017; 61(8):1600878.
[147]

Otto M, Breinholt J, Westergaard N. Metformin inhibits glycogen synthesis and gluconeogenesis in cultured rat hepatocytes. Diabetes Obes Metab 2003; 5(3):189-94.
[148]

Song HP, Zhang H, Hu R, Xiao HH, Guo H, Yuan WH, et al. A strategy to discover lead chemome from traditional Chinese medicines based on natural chromatogram-effect correlation (NCEC) and natural structure-effect correlation (NSEC): Mahonia bealei and Mahonia fortunei as a case study. J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1181:122922.
[149]

Zappavigna S, Vanacore D, Lama S, Potenza N, Russo A, Ferranti P, et al. Silybin-induced apoptosis occurs in parallel to the increase of ceramides synthesis and miRNAs secretion in human hepatocarcinoma cells. Int J Mol Sci 2019; 20(9):2190.
[150]

Wang G, Guo X, Chen H, Lin T, Xu Y, Chen Q, et al. A resveratrol analog, phoyunbene B, induces G2/M cell cycle arrest and apoptosis in HepG2 liver cancer cells. Bioorg Med Chem Lett 2012; 22(5):2114-8.
[151]

Zhao Y, Ren J, Hillier J, Lu W, Jones EY. Caffeine inhibits Notum activity by binding at the catalytic pocket. Commun Biol 2020; 3(1):555.
[152]

Zhai M, Li B, Duan W, Jing L, Zhang B, Zhang M, et al. Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis. J Pineal Res 2017; 63(2):e12419.
[153]

Agil A, Rosado I, Ruiz R, Figueroa A, Zen N, Fernandez-Vazquez G. Melatonin improves glucose homeostasis in young Zucker diabetic fatty rats. J Pineal Res 2012; 52(2):203-10.
[154]

Carocci A, Catalano A, Bruno C, Lovece A, Roselli MG, Cavalluzzi MM, et al. N-(Phenoxyalkyl)amides as MT(1) and MT(2) ligands: antioxidant properties and inhibition of Ca2+/CaM-dependent kinase II. Bioorg Med Chem 2013; 21(4):847-51.
[155]

Kim CS, Bae M, Oh J, Subedi L, Suh WS, Choi SZ, et al. Anti-neurodegenerative biflavonoid glycosides from impatiens balsamina. J Nat Prod 2017; 80(2):471-8.
[156]

Lin D, Yan Z, Chen A, Ye J, Hu A, Liu J, et al. Anti-proliferative activity and structure—activity relationship of honokiol derivatives. Bioorg Med Chem 2019; 27(16):3729-34.
[157]

Wei L, Zhou Y, Qiao C, Ni T, Li Z, You Q, et al. Oroxylin A inhibits glycolysis-dependent proliferation of human breast cancer via promoting SIRT3-mediated SOD2 transcription and HIF1alpha destabilization. Cell Death Dis 2015; 6(4):e1714.
[158]

Dai Q, Yin Q, Wei L, Zhou Y, Qiao C, Guo Y, et al. Oroxylin A regulates glucose metabolism in response to hypoxic stress with the involvement of hypoxia-inducible factor-1 in human hepatoma HepG2 cells. Mol Carcinog 2016; 55(8):1275-89.
[159]

Fu W, Wang J, Yu L, Zhao L, Lu N, You Q, et al. Synthesis and biological evaluation of 7-O-modified oroxylin A derivatives. Bioorg Med Chem Lett 2012; 22(2):1118-21.
[160]

Quang TH, Ngan NT, Minh CV, Kiem PV, Tai BH, Thao NP, et al. Anti-inflammatory and PPAR transactivational effects of secondary metabolites from the roots of Asarum sieboldii. Bioorg Med Chem Lett 2012; 22(7):2527-33.
[161]

Toda S, Shirataki Y. Inhibitory effects of isoflavones in Sophora mooracrotiana on lipid peroxidation by superoxide. Pharm Biol 2002; 40(6):422-4.
[162]

Ji XY, Xue ST, Zhan YC, Shen JJ, Wu LT, Jin J, et al. Design, synthesis and antiproliferative activity of a novel class of indole-2-carboxylate derivatives. Eur J Med Chem 2014; 83:409-18.
[163]

Devabattula G, Bakchi B, Sharma A, Panda B, Madhavi V, Godugu C. 7-Hydroxy-3-( 4′-methoxyphenyl) coumarin (C12) attenuates bleomycin-induced acute lung injury and fibrosis through activation of SIRT3. Biochem Pharmacol 2025; 232:116723.
[164]

Takahashi D, Oyunzul L, Onoue S, Ito Y, Uchida S, Simsek R, et al. Structure-activity relationships of receptor binding of 1,4-dihydropyridine derivatives. Biol Pharm Bull 2008; 31(3):473-9.
[165]

Ahn J, Chae HS, Chin YW, Kim J. Alkaloids from aerial parts of Houttuynia cordata and their anti-inflammatory activity. Bioorg Med Chem Lett 2017; 27(12):2807-11.
[166]

Buler M, Aatsinki SM, Izzi V, Hakkola J. Metformin reduces hepatic expression of SIRT3, the mitochondrial deacetylase controlling energy metabolism. PLoS One 2012; 7(11):e49863.
[167]

Li H, Wang XK, Tang M, Lei L, Li JR, Sun H, et al. Bacteroides thetaiotaomicron ameliorates mouse hepatic steatosis through regulating gut microbial composition, gut-liver folate and unsaturated fatty acids metabolism. Gut Microbes 2024; 16(1):2304159.
[168]

Kong WJ, Vernieri C, Foiani M, Jiang JD. Berberine in the treatment of metabolism-related chronic diseases: a drug cloud (dCloud) effect to target multifactorial disorders. Pharmacol Ther 2020; 209:107496.
[169]

Brandauer J, Vienberg SG, Andersen MA, Ringholm S, Risis S, Larsen PS, et al. AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle. J Physiol 2013; 591(20):5207-20.
[170]

Teodoro JS, Duarte FV, Gomes AP, Varela AT, Peixoto FM, Rolo AP, et al. Berberine reverts hepatic mitochondrial dysfunction in high-fat fed rats: a possible role for SIRT 3 activation. Mitochondrion 2013; 13(6):637-46.
[171]

Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 2004; 10(12):1344-51.
[172]

Lan J, Zhao Y, Dong F, Yan Z, Zheng W, Fan J, et al. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol 2015; 161:69-81.
[173]

Wong VW, Neff GW, Di Bisceglie AM, Bai R, Cheng J, Yu M, et al. HTD1801 demonstrates promising potential for histologic improvements in metabolic dysfunction-associated steatohepatitis in both a preclinical and phase 2 study. Clin Mol Hepatol 2025; 31(3):1071-83.
[174]

Ji L, Ma J, Ma Y, Cheng Z, Gan S, Yuan G, et al. Berberine ursodeoxycholate for the treatment of type 2 diabetes: a randomized clinical trial. JAMA Netw Open 2025; 8(3):e2462185.
[175]

Zhang B, Xu D, She L, Wang Z, Yang N, Sun R, et al. Silybin inhibits NLRP 3 inflammasome assembly through the NAD+/SIRT2 pathway in mice with nonalcoholic fatty liver disease. FASEB J 2018; 32(2):757-67.
[176]

Cai J, Zhu Y, Li X, Deng G, Han Y, Yuan F, et al. Liposomal silybin improves glucose and lipid metabolisms in type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease via AMPK/TGF-beta1/Smad signaling. Tohoku J Exp Med 2023; 261(4):257-65.
[177]

Harikumar KB, Aggarwal BB. Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle 2008; 7(8):1020-35.
[178]

Ning L, Rui X, Guorui L, Tinglv F, Donghang L, Chenzhen X, et al. A novel mechanism for the protection against acute lung injury by melatonin: mitochondrial quality control of lung epithelial cells is preserved through SIRT3-dependent deacetylation of SOD2. Cell Mol Life Sci 2022; 79(12):610.
[179]

Reiter RJ, Tan DX, Rosales-Corral S, Galano A, Jou MJ, Acuna-Castroviejo D. Melatonin mitigates mitochondrial meltdown: interactions with SIRT3. Int J Mol Sci 2018; 19(8):2439.
[180]

Song C, Peng W, Yin S, Zhao J, Fu B, Zhang J, et al. Melatonin improves age-induced fertility decline and attenuates ovarian mitochondrial oxidative stress in mice. Sci Rep 2016; 6(1):35165.
[181]

Yu L, Gong B, Duan W, Fan C, Zhang J, Li Z, et al. Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1alpha-SIRT3 signaling. Sci Rep 2017; 7(1):41337.
[182]

Andreani T, Cheng R, Elbadri K, Ferro C, Menezes T, Dos Santos MR, et al. Natural compounds-based nanomedicines for cancer treatment: future directions and challenges. Drug Deliv Transl Res 2024; 14(10):2845-916.
[183]

Trevino-Saldana N, Garcia-Rivas G. Regulation of sirtuin-mediated protein deacetylation by cardioprotective phytochemical. Oxid Med Cell Longev 2017; 2017(1):1750306.
[184]

Zhu R, Zeng G, Chen Y, Zhang Q, Liu B, Liu J, et al. Oroxylin A accelerates liver regeneration in CCl4-induced acute liver injury mice. PLoS One 2013; 8(8):e71612.
[185]

Zhang J, Meruvu S, Bedi YS, Chau J, Arguelles A, Rucker R, et al. Pyrroloquinoline quinone increases the expression and activity of SIRT1 and -3 genes in HepG2 cells. Nutr Res 2015; 35(9):844-9.
[186]

Mai A, Valente S, Meade S, Carafa V, Tardugno M, Nebbioso A, et al. Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors. J Med Chem 2009; 52(17):5496-504.
[187]

Zwergel C, Aventaggiato M, Garbo S, Di Bello E, Fassari B, Noce B, et al. Novel 1,4-dihydropyridines as specific binders and activators of SIRT3 impair cell viability and clonogenicity and downregulate hypoxia-induced targets in cancer cells. J Med Chem 2023; 66(14):9622-41.
[188]

Shen H, Ma W, Hu Y, Liu Y, Song Y, Fu L, et al. Mitochondrial sirtuins in cancer: a revisited review from molecular mechanisms to therapeutic strategies. Theranostics 2024; 14(7):2993-3013.
[189]

Wang YJ, Paneni F, Stein S, Matter CM. Modulating sirtuin biology and nicotinamide adenine diphosphate metabolism in cardiovascular disease—from bench to bedside. Front Physiol 2021; 12:755060.
[190]

Yue Z, Ma Y, You J, Li Z, Ding Y, He P, et al. NMNAT 3 is involved in the protective effect of SIRT3 in Ang II-induced cardiac hypertrophy. Exp Cell Res 2016; 347(2):261-73.
[191]

Nadtochiy SM, Wang YT, Nehrke K, Munger J, Brookes PS. Cardioprotection by nicotinamide mononucleotide (NMN): involvement of glycolysis and acidic pH. J Mol Cell Cardiol 2018; 121:155-62.
[192]

Alhazzazi TY, Kamarajan P, Xu Y, Ai T, Chen L, Verdin E, et al. A novel sirtuin-3 inhibitor, LC-0296, inhibits cell survival and proliferation, and promotes apoptosis of head and neck cancer cells. Anticancer Res 2016; 36(1):49-60.
[193]

Gorska-Ponikowska M, Kuban-Jankowska A, Eisler SA, Perricone U, Lo Bosco G, Barone G, et al. 2-Methoxyestradiol affects mitochondrial biogenesis pathway and succinate dehydrogenase complex flavoprotein subunit a in osteosarcoma cancer cells. Cancer Genom Proteom 2018; 15(1):73-89.
[194]

Sann KM, Rahman M, Thu MM. Immunotherapy for type 1 diabetes. M&TOD 2024; 4(4):37.
[195]

Desalegn H, Farias R, Hudson D, Idalsoaga F, Cabrera D, Diaz LA, et al. Prevention and control of risk factors in metabolic and alcohol-associated steatotic liver disease. M&TOD 2024; 4(3):25.
PDF (2513KB)

4555

Accesses

0

Citation

Detail
Sections
Recommended

/

〈 〉