The conflicting role of SIRT3 as therapeutic target in cancer
Patrick M. Schaefer, Devyani Bhosale
Author Information

1 Center for Mitochondrial andEpigenomic Medicine, Division of Human Genetics, Department of Pediatrics,Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

2 Department of Pharmaceutical Sciences, Philadelphia Collegeof Pharmacy, University of the Sciences, Philadelphia, PA 19104, USA.


Citation Information
Schaefer and Bhosale, J Life Sci, Vol. 3, No. 2, June 2021:19-42


Mitochondria are increasingly recognized as key factors in cancer, affecting a multitude of tumor hallmarks. Likewise, sirtuin 3, a master regulator of mitochondrial function, has gained attention as a therapeutic target in cancer. As a main mediator of calorie restriction, sirtuin 3 inhibits anabolic reactions and cell proliferation, acting as a tumor suppressor. At the same time, sirtuin 3 protects the cell during nutrient stress by regulating cell death and DNA repair, thereby acting as an oncogene. Here we discuss this conflicting role of sirtuin 3 in cancer and evaluate the therapeutic potential of sirtuin 3 activators and inhibitors in different cancers. Keywords: Sirtuin, SIRT3, Cancer, Mitochondria


The lifetime risk of developing cancer is greater than 35% in the United States, and cancer is continuously among the three most common causes of death worldwide (1, 2). While tumors are very heterogeneous in their phenotype and underlying molecular changes, there are common characteristics that result in uncontrolled proliferation and malignancy. These hallmarks include proliferative signaling, genome instability, immune evasion, resistance to cell death and a deregulation of cellular energetics (3, 4).

The preference of tumors for anaerobic metabolism in the presence of oxygen, known as the Warburg effect, was discovered almost 100 years ago (5, 6). However, only within the last decade has a better understanding of this phenotype emerged. While oxidative phosphorylation is the most efficient with respect to ATP production, carbon is oxidized to CO2 and not available for biomass production. To maintain a high proliferation rate, tumor cells need to use glycolytic and TCA cycle intermediates such as Acetyl-CoA, amino acids, or ribose for biogenesis at the expense of efficient energy production (7, 8). These insights have resulted in a renewed focus on the role of mitochondria in cancer (9). Mitochondria are not only crucial in providing macromolecular precursors for cell proliferation but are also at the crossroads of many other hallmarks of cancer. Mitochondria are the major source of reactive oxygen species (ROS) in the cell, which can result in oxidative damage and mutations in DNA. Similarly, mitochondria regulate the antioxidative response (10) and DNA repair via the redox status and PARP1 (11), demonstrating a key role of mitochondria in genome stability. With respect to immune evasion, mitochondria were shown to regulate immune cell proliferation (12) and inflammatory response (13), suggesting a central role in the immune system and cancer-associated immune evasion (14, 15). Lastly, mitochondria are well known for their role in apoptotic cell death (16) and a dysregulation of mitochondrial apoptotic signaling was associated with cancer (17, 18). Taken together, mitochondria are a common link between the hallmarks of cancer. This emphasizes mitochondrial metabolism and its regulators, such as sirtuins, as promising targets for therapeutic intervention in cancer.

Sirtuins, or its homolog Sir-2, were first discovered in yeast and C. elegans in response to calorie restriction mediating an extended lifespan (19, 20). Sir-2 was described as a class III histone deacetylase, removing acetyl-groups from lysine residues on histones in an NAD+ dependent manner, thereby resulting in gene silencing (21).

In mammalian cells there are 7 sirtuin isoforms (SIRT1-SIRT7). They differ with respect to subcellular localization and substrate specificity. While SIRT1, 2, 6, 7 are predominantly localized in the nucleus or cytoplasm, SIRT3-5 are found mostly in the mitochondria (22). Sirtuins are not confined to histones as substrates but can perform posttranslational modifications on many non-histone proteins, resulting in either activation or inhibition of these enzymes. While deacetylation is the predominant modification mediated by sirtuins, some isoforms such as SIRT6 can remove larger Acyl-groups (23) or are involved in ADP-ribosylation (24).

All sirtuins display two core domains, a Rossmann fold domain common in nucleotide binding enzymes (25) and a zinc binding domain (26). Due to their NAD+ dependency, sirtuins function as cellular energy sensors detecting a low energy state by an increased NAD+/NADH ratio (19, 27), thereupon modifying gene expression or enzyme activity. Sirtuin activation generally results in a downstream induction of catabolism along with a reduction in anabolic reactions. In addition to their function as energy sensors and metabolic regulators (28), sirtuins were shown to be involved in cellular stress (29), the antioxidative response (22,30), inflammation (31,32) and DNA repair (33,34). Taken together, sirtuins are suggested to be a central hub for mitochondrial-nuclear interactions and for regulating cellular metabolism.

Dysregulation of the sirtuins has been associated with many disorders, such as aging (20,22,35), type II diabetes (36,37), cardiovascular disease (38-40), neurodegeneration (41,42), and cancer (43,44). With respect to cancer, it was demonstrated that several sirtuin knockout mice were more prone to develop tumors (45-47) suggesting sirtuin activation as a promising therapeutic target in cancer. However, recent evidence indicates a more conflicting role of sirtuins in tumorigenesis (48,49) with some tumors showing an upregulation of sirtuin expression (50,51). Given the crucial role of mitochondria in cancer, SIRT3 is of paramount interest since it is the predominant mitochondrial sirtuin. In this review we focus on SIRT3 aiming to unravel its dichotomous role in cancer, and evaluate activators and inhibitors of SIRT3 as therapeutic interventions in different malignancies.


SIRT3 is the major mitochondrial sirtuin and plays a key role in regulating mitochondrial enzymes via acetylation (52,53). It is found in most cell types and tissues with the highest levels in kidney, brain, heart, and liver (54). It is expressed as a 44kDa cytosolic protein containing an N-terminal mitochondrial targeting sequence. Proteolytic processing by the mitochondrial processing peptidase removes 101 amino acids on the N-terminus thereby resulting in activation of SIRT3 in the mitochondria. It is debated whether SIRT3 is exclusively found in the mitochondria (55) or if it translocates from the nucleus to the mitochondria upon cell stress (56). It appears clear that SIRT3 mainly plays a role in mitochondrial adaption to stress (57).

Regulation of SIRT3

Different stressors are known to regulate SIRT3 such as metabolic, oxidative, or genotoxic stress (58). Transcriptionally, an antioxidant response element upstream of SIRT3 was reported to regulate SIRT3 expression via the Nrf2-Keap axis in response to metabolic stress (59). On the protein level, it was suggested that SIRT3 can be targeted for degradation by the E3 ligase in response to DNA damage(60). In addition, PARP1 activation can deplete SIRT3 of NAD+ given a much lower Km of PARP1 for NAD+ (61,62). It is well known that NAD+ levels play an important role in stimulating SIRT3 activity (63). Conversely, nicotinamide, a product of the sirtuin reaction, was shown to mediate a feedback inhibition by binding to the C-pocket (64). There is some controversy with respect to sirtuin sensitivity for NADH and whether sirtuins sense the NAD+/nicotinamide ratio or the NAD+/NADH ratio (65). Interestingly, while sirtuin activity is stimulated by NAD+, sirtuin expression correlates with a low NAD+/NADH ratio (66). This suggests a differential effect of nuclear versus mitochondrial NAD+/NADH redox state on SIRT3 expression and activity respectively.

Physiological Function and Substrates of SIRT3

The main function of SIRT3 is the regulation of mitochondrial energy metabolism. SIRT3 deacetylates and thereby activates several enzymes of the TCA cycle such as pyruvate dehydrogenase (67), isocitrate dehydrogenase (IDH) (68) or Acetyl-CoA synthetase 2 (69). Additionally, it activates the mitochondrial electron transport system directly by deacetylating NDUFA9, a complex I subunit (70), and succinate dehydrogenase (71), complex II of the electron transport chain. Given the role of SIRT3 in metabolic adaptation to nutrient deprivation, SIRT3 stimulates fatty acid oxidation by activating long acyl chain dehydrogenases (57) and ketogenesis by activating the rate limiting enzyme 3-hydroxy-3-methylglutaryl-CoA synthase (72). Similarly, amino acid oxidation (73) and the associated urea cycle are activated by SIRT3 (74). At the same time, SIRT3 helps to preserve nutrient availability by limiting glucose uptake via Cyclophilin D (CYP-D) activation and subsequent dissociation of hexokinase 2 from the mitochondria (75). Taken together, SIRT3 stimulates catabolism and mediates a metabolic switch from glycolysis to oxidative phosphorylation.

Cell and nutrient stress as well as increased activity of the electron transport system are associated with increased ROS production. SIRT3 promotes the antioxidant response by activating Manganese Superoxide Dismutase (MnSOD) directly via deacetylation (76) and indirectly via FOXO3a-mediated upregulation (77). In addition, it stimulates NADPH production by IDH (68) and inactivates glutamic-oxaloacetic transaminase 2 (GOT2), thereby blocking the malate-aspartate shuttle (78). This maintains reducing equivalents in the cytosol, boosting the glutathione antioxidant system.



Figure 1: SIRT3 regulates Cell Metabolism and Health

SIRT3 deacetylates many mitochondrial proteins, thereby regulating a multitude of cellular functions. The functional cornerstones are an upregulation (indicated by blue) of mitochondrial energy metabolism, a downregulation (indicated by red) of reactive oxygen species, prevention of cell death and an inhibition of proliferation. Selected deacetylation targets mediating the physiological functions of SIRT3 are indicated on the arrows. Created with

SIRT3 also plays a role in regulating DNA damage and cell death. SIRT3 was reported to deacetylate p53, which promotes its proteasomal degradation (79). Conversely, SIRT3 prevents degradation of 8-oxoguanine-DNA glycosylase 1 (80), a crucial enzyme in mitochondrial DNA repair. With respect to cell death, it was reported that SIRT3 activates Ku70, which subsequently binds Bax and prevents stress-induced cell death (81). Similarly, opening of the mitochondrial transition pore by CYP-D inactivation is reduced (82) preventing cell death due to mitochondrial calcium overload.

In summary, SIRT3 orchestrates the adaptation of mitochondrial energy metabolism. Upon sensing a low energy state via the redox ratio, it stimulates catabolic reactions and mitochondrial energy production. At the same time, it downregulates cell growth/replication but also protects the cell from ROS, DNA damage, or cell death (Figure 1).

SIRT3 in Cancer

Cancer cells can be distinguished from normal cells based on several key characteristics such as insensitivity to growth inhibitory signals and cell death resistance mechanisms, increased proliferative signaling, sustained angiogenesis, deregulation of metabolic pathways, genomic instability, increased inflammation, and tumor cell mobility (4). As such, deregulation of several physiological functions mediated by SIRT3 implicate a role for the mitochondrial sirtuin in cancer development. This association was underlined by an early study in SIRT3 knockout mice that demonstrated increased development of ER/PR-positive mammary tumors (45). SIRT3 deregulation has further been observed across several tumor subtypes. Mitochondrial SIRT3 can act as a tumor promoter or suppressor depending on the tumor profile and distinct molecular signatures of the cancer cells (Figure 2).


Figure 2:  SIRT3 as Tumor Suppressor or Oncogene in different Tumors

SIRT3 mediates its tumor suppressor or oncogenic function by modulating cellular physiology differentially in a variety of tumors. Created with

SIRT3 as Tumor Suppressor

A strong reliance on glycolytic energy metabolism to produce substrates for anabolic reactions is a hallmark of many tumors. SIRT3, in contrast, promotes a switch towards oxidative phosphorylation, thereby acting as a tumor suppressor. For example, in breast carcinoma SIRT3 inhibits glycolysis by deacetylating cyclophilin D, which leads to the dissociation of hexokinase II from the outer mitochondrial membrane protein voltage-dependent anion channel (83).  Additionally, SIRT3-mediated stabilization of p53 via PTEN and MDM2 was shown to inhibit glycolysis and tumor cell proliferation by positive transcriptional regulation of genes involved in mitochondrial oxidative phosphorylation (84-86). A recent study in cholangiocarcinoma cells demonstrates the anti-Warburg effect of SIRT3 by inhibition of the hypoxia inducible factor 1α (HIF-1α)/pyruvate dehydrogenase kinase 1 (PDK1) pathway (87). SIRT3-mediated ROS depletion is also known to promote tumor inhibition. A study in SIRT3 knockout primary mouse embryonic fibroblasts demonstrated increased activation of HIF-1α, which is involved in transcriptional regulation of several glycolytic genes known to promote tumorigenesis (88,89). Activation of prolyl hydroxylases by SIRT3 was found to be responsible for destabilization of HIF-1α and mitigated its tumor promoting effects (90,91). Moreover, studies in prostate cancer reported that ROS depletion by SIRT3 could suppress the PI3K/Akt pathway resulting in ubiquitination and degradation of oncoprotein c-Myc, thus inhibiting tumor progression (92).

SIRT3 does not only influence proliferation via the abundance of glycolytic intermediates, but also regulates multiple pathways associated with proliferation, cell migration, and renewal. Given the role of SIRT3 in caloric restriction and downregulation of anabolic reactions a tumor suppressor role would be expected. SIRT3 mediated inactivation of glutamate oxaloacetate transaminase 2 in pancreatic cancer was shown to arrest proliferation and tumor growth (78). Deactivation of the proto-oncogene F-box protein S-phase kinase associated protein 2 by SIRT3 could also inhibit cancer cell progression and migration (93). SIRT3 was found to prevent hyperacetylation of enoyl-CoA hydratase 1 (ECHS1) in cancer, thereby inhibiting mTOR regulated proliferation (94). Furthermore, modulation of ROS signaling by SIRT3 was found to be relevant to tumor cell migration. Depletion of ROS levels by SIRT3 demonstrated diminished focal adhesion kinase (FAK) phosphorylation, which is required for breast cancer metastasis (95). SIRT3 was also shown to inhibit epithelial-to-mesenchymal transition (EMT) and metastasis in ovarian cancer cells by downregulation of Twist (96). Upregulated levels of SIRT3 in metastatic prostate cancer were shown to induce the inhibition of Wnt/β-catenin pathway, a central regulator of EMT and tumor metastasis (97). Additionally, SIRT3 mediated inhibition of cellular migration and metastasis have been demonstrated in hepatocellular carcinoma (98) and pancreatic ductal cell carcinoma (99).

Tumor-modulating effects of SIRT3 can also be attributed to its regulation of DNA repair and programmed cell death. As a tumor suppressor SIRT3 works to promote apoptosis. In HepG2 cells SIRT3 was found to induce Bax and Fas regulated apoptosis. This was mechanistically shown to be an effect of SIRT3-mediated upregulation of p53 and MnSOD (100). SIRT3 was also found to induce apoptosis in hepatocellular carcinoma by deacetylation of glycogen synthase kinase-3β, which further resulted in increased expression and mitochondrial translocation of Bax (101). Additionally, downregulation of Bcl-2 and JNK2 by SIRT3 was shown to contribute to apoptosis in hepatocellular carcinoma (102). In human lung adenocarcinoma tissue upregulated levels of SIRT3 results in increased translocation of apoptosis inducing factor (AIF) to the nucleus with higher levels of p53, p21, and depletion of ROS. This ultimately results in increased apoptosis (103). A recent study in small-cell lung cancer demonstrated that SIRT3 can inhibit tumor progression by promoting apoptosis and necroptosis via modulation of ubiquitination-mediated proteasomal degradation of mutant p53 protein (104). Ovarian cancer cell lines with increased expression of SIRT3 have also demonstrated increased sensitivity to metformin-induced apoptosis (105).

SIRT3 as Oncogene

Numerous studies over the past decade have also demonstrated the tumor promoting effects of SIRT3 across different cancers (Figure 2). This controversial role of SIRT3 as an oncogene likely arises from differential regulation of SIRT3-mediated cellular pathways in certain tumor settings. For example, increased protein and mRNA levels of SIRT3 were reported in non-small cell lung cancer tissues, and SIRT3 was found to regulate the activation of Akt promoting tumor malignancy (106). PTEN-deficient lung tissues have also demonstrated increased levels of SIRT3, which correlate with depleted p53 levels. SIRT3 was found to be responsible for ubiquitination and proteasomal degradation of p53 (79). SIRT3 was reported to activate lactate dehydrogenase in gastric cancer cells resulting in glycolysis and promotion of tumorigenesis (107). Hematological cancers that depend on oxidative phosphorylation also demonstrate an oncogenic role for SIRT3 (108). SIRT3 was found to promote lymphomagenesis in diffuse large B cell lymphomas by regulating TCA cycle via glutamate dehydrogenase (109). SIRT3 was further shown to deacetylate IDH2, a critical enzyme participating in forward Krebs cycle. The activation of IDH2 by SIRT3 promotes carcinogenesis in multiple myeloma cell lines (110).

SIRT3 can also participate in stimulation of proliferative signaling pathways and promote tumorigenesis.  For example, SIRT3-mediated activation of nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) was shown to result in increased cellular proliferation and glycolytic flux (111). Similarly, SIRT3 activates the pyrroline-5-carboxylate reductase 1 (PYCR1) thereby stimulating proliferation (112). An increased expression of SIRT3 in lymph node positive breast cancer metastasis is also believed to contribute to the survival of aggressive cancer phenotypes. SIRT3-mediated deacetylation of serine hydroxymethyl-transferase 2 (SHMT2) was demonstrated to inhibit its lysosome-dependent degradation and contributed to colorectal cancer development (113). Other studies in colorectal cancer have demonstrated that SIRT3 activates the Akt/PTEN pathway, regulates transcription of metastatic genes like EGFR and BRAF, and promotes cancer cell migration and proliferation (114). Likewise, a study in cervical cancer cells revealed that SIRT3 deacetylated Acetyl-CoA carboxylase and reprogrammed fatty acid metabolism to promote migration and invasion (115).

As a central mitochondrial deacetylase, SIRT3 can respond to metabolic and genotoxic stress and protect cancer cells from apoptosis. SIRT3 was shown to deacetylate and bind with Ku70, which augmented Ku70-Bax interactions and prevented translocation of Bax to the mitochondria. This resulted in inhibition of apoptosis in HeLa cells (81). Overexpression of SIRT3 in oral squamous carcinoma cells is also shown to correlate with anoikis, apoptosis triggered by loss of extracellular matrix, and cell survival. Increased expression of SIRT3 in anoikis-resistant oral cancer was found to be accompanied by lower expression of receptor interacting protein, which can act as a negative regulator of SIRT3 (116). SIRT3-mediated deacetylation of histone H3 was also found to promote nonhomologous end joining repair. Histone H3 is known to be involved in the response to DNA damage and is found to be colocalized with γH2AX implicating a role for SIRT3 in maintenance of genomic stability in tumors (117). Likewise, another study reported that SIRT3 modulates the activity of human 8-oxoguanine-DNA glycosylase 1, a DNA repair enzyme, and assists in the response to mitochondrial DNA damage preventing stress mediated apoptosis (80).

Taken together, SIRT3 can act as a tumor suppressor or oncogene dependent on the specific tumor by regulating important tumor hallmarks such as energy metabolism, ROS, apoptosis, and proliferation.

Therapeutic targeting of SIRT3 in Cancer

As SIRT3 is implicated in the pathogenesis of cancer and other diseases, numerous compounds have been identified and studied for their activity on SIRT3. These molecules can regulate the activity of SIRT3 by either influencing its expression or by modulating its deacetylation function (118). Based on their effect, SIRT3 modulators can be broadly classified as SIRT3 activators or inhibitors (Table 1) (119).

SIRT3 Activators

Given the tumor suppressive function of SIRT3 across several cancer types, SIRT3 activation can prove to be an effective strategy. Endogenous regulators like nicotinamide riboside or nicotinamide mononucleotide can boost the intracellular levels of NAD+ and thereby stimulate SIRT3 (120). For example, it has been shown that nicotinamide mononucleotide can inhibit tumor growth and metastasis in mice (121). However, these endogenous regulators are not specific to SIRT3 but activate all sirtuins and directly affect cellular energy metabolism independent of the sirtuins.

Among the other compounds studied for specific SIRT3 activation, Honokiol, isolated from the bark of Magnolia officinalis, has shown great efficacy in the activation of SIRT3 (122). In vitro and in vivo studies with Honokiol in cancers of the breast, colon, prostate, liver, and squamous cell lung carcinomas have demonstrated promising results. However, most of its anti-cancer activity is attributed to its effects on other molecular targets such as NF-κb, STAT3, EGFR, mTOR, β-catenin and HIF1α, which are also known to be involved in pathways of cell survival, proliferation, and metabolism (123-128). Similarly, Silybin demonstrates weak SIRT3 activation (129,130) and has been found to suppress tumor growth (131,132), however a connection between both functions of Silybin have not yet been established. Resveratrol (119, 133, 134) and Piceatannol (133, 135,136) were found to activate most sirtuins but there are controversial reports of activation or inhibition of SIRT3 (137,138) and conclusive evidence supporting their role in SIRT3 mediated anti-cancer activity is lacking. More research into the discovery of synthetic, specific SIRT3 activators is needed to reveal a comprehensive overview of the potential of SIRT3 activation in different cancers as current activators lack specificity.

SIRT3 Inhibitors

On the contrary, improved understanding of the deacetylation process and identification of the crystal structure of SIRT3 has prompted research into the development of SIRT3 inhibitors. Using high throughput and in silico screening, several molecules with a wide range of core structures have been identified for SIRT3 inhibition. Of the numerous strategies employed, catalytic mechanism- based inhibition of SIRT3 has been widely studied. Nicotinamide serves as a natural sirtuin inhibitory molecule by binding to a conserved region in the sirtuin catalytic site and promoting a reverse base-exchange reaction instead of the deacetylation reaction (139). The chemo-preventive potential of nicotinamide was also demonstrated in keratinocyte cancers (140). However, the non-specific inhibition of all sirtuin isoforms and its rapid conversion to NAD+ limit the potential of nicotinamide for use in the treatment of cancer and other diseases. Thus, nicotinamide analogues have been developed for possible sirtuin inhibition. 3-TYP is a highly specific SIRT3 inhibitor (141), whereas Selisistat (or EX-527), a SIRT1, SIRT2 and SIRT3 inhibitor, has shown to work synergistically with Wee1 in lung cancer cells to promote growth inhibition and apoptosis (142-144).

Another strategy for the development of sirtuin inhibitors employs substrate specific competition. 4’-bromo resveratrol, an analogue of Resveratrol, was found to suppress SIRT1 and SIRT3 in melanoma where the targeted sirtuins had a proliferative role (145,146). It was observed that this dual inhibition of SIRT1 and SIRT3 was accompanied by induction of caspase-dependent apoptosis, inhibition of migratory potential, arrest in G1 phase, and ablation of aerobic glycolysis (146). Several SIRT3 inhibitors have been developed using a SIRT3-structure based approach but their biological activity has not been reported (147).

Chemical library screening-based development of SIRT3 inhibitors is another efficient strategy to identify novel SIRT3 inhibitors. A study utilizing self-assembled monolayer desorption/ionization mass spectrometry (SAMDI-MS) was used to screen small molecules for SIRT3 inhibition activity. This led to the discovery of SDX-437, which has an IC50 of 700nM and is one of the strongest SIRT3 inhibitors identified so far but has not yet been tested for potential anti-cancer activity (148). In contrast, Tenovin-6, a p53 activator and non-competitive inhibitor of SIRT3, has shown anti-tumor activity mostly through regulation of SIRT1, SIRT2 and to a lesser extent through SIRT3 (149,150). Minnelide, a water-soluble prodrug for diterpene tri-epoxide triptolide, was shown to inhibit the expression of SIRT3 in p53-deficient cancer cells and promoted mitochondrial dysfunction and upregulation of pro-apoptotic genes via mitigation of NF-κB signaling (151,152).

 Table 1: Activators and Inhibitors of SIRT3


Chemical Structure



SIRT3 Activators



Increased SIRT3 levels and activity (122)

Not sirtuin-specific (123)

Cardiomyopathy (122)

Multiple cancers (123)



Increased SIRT3 expression

Not sirtuin-specific (129)

Acute kidney injury (129)

Liver disease (130)

Cancer (131, 132)

Nicotinamide Riboside


Boosts NAD+ levels

Activates all sirtuins

 alters energy metabolism



Mitochondrial disorders (120)

SIRT3 Inhibitors



Feedback inhibition (139)

Multiple cancers (140)



NAD+ competitive SIRT3 inhibitor (141)

Acute myeloid leukemia (156)



Occupies NAD+ binding pocket, Inhibitor of SIRT1, SIRT2, SIRT3 (143)

Lung Cancer (142)

Huntington’s disease (144)



Substrate competitive SIRT1 and SIRT3 inhibitor (145)

Melanoma (146)



Inhibitor of SIRT3 > SIRT1




SIRT1, SIRT2 > SIRT3 inhibitor (149)

Gastric cancer (150)



Regulates SIRT3 expression and proteasomal degradation (152)

Non-small cell lung carcinoma (151)



Binds to canonical and allosteric inhibitor binding sites of SIRT3 (153)

Osteosarcoma (153)


2-Methoxyestradiol, a natural derivative of 17β-estradiol was also found to inhibit the activity of SIRT3 by binding to both the canonical and allosteric inhibitor binding sites ultimately causing inhibition of mitochondrial biogenesis in osteosarcoma cancer cell model (153).

The use of Encoded library technology for screening of DNA encoded small molecules identified pan-inhibitors of SIRT1/2/3 such as carboxamides, which block the nicotinamide binding site (154). Additionally, the application of techniques such as DNA encoded Dynamic combinatorial library has led to the discovery of more selective and potent SIRT3 inhibitory ligands compared to the pan-sirtuin inhibitors (155).  However, most of these compounds have yet to be evaluated for their efficacy in experimental models of cancer.

Taken together, the discovery of new and improved compounds targeting SIRT3 activity for therapeutic benefit is highly desired. Application of scientific drug design strategies will be particularly important to achieve this.


SIRT3 is a crucial conductor of mitochondrial activity and cell metabolism thereby regulating important hallmarks of cancer. Alterations in SIRT3 and its downstream pathways have been found in many tumors emphasizing its involvement in cancer. However, SIRT3 cannot be pinpointed as a universal tumor suppressor or oncogene (48). One future challenge will be to elucidate the role of SIRT3 in different types and stages of tumors and to identify molecular tumor profiles that determine the divergent role of SIRT3. For example, SIRT3 generally acts more as a tumor suppressor in tumors that heavily rely on glycolysis as opposed to its oncogenic role in lymphomas, which rely more on oxidative energy metabolism. It could also be hypothesized that SIRT3 activation might work well preventing tumor growth in early stages due to its antiproliferative effect but is less effective in later stages because of its protective effect on cell stress. Future studies correlating the function of SIRT3 in specific tumors with their metabolic or expression profile will shed light on potential applications for SIRT3 modulators as cancer therapeutics in a personalized medicine approach (Figure 3).

Given the complex role of SIRT3 in cancer, application of SIRT3 activators or inhibitors needs to be carefully evaluated depending on the type and location of cancer. Application of SIRT3 activators might lead to increased carcinogenesis, whereas SIRT3 inhibition could culminate into multiple organ toxicities. As such, the development and application of targeted drug delivery systems might help overcome drawbacks associated with nonspecific effects of SIRT3 modulation. Similarly, combination of SIRT3 modulators with chemotherapeutics might be a promising approach given that SIRT3 can confer chemoresistance in some tumors (156). Despite the identification of several SIRT3 modulators, none have been approved for therapeutic use. Hence, an improved understanding of the contextual role of SIRT3 will be required for successful development and application of SIRT3 modulators as therapeutic anti-cancer drugs


Figure 3: SIRT3 as potential therapeutic Target in Cancer

SIRT3 can act as either a tumor suppressor or oncogene. Combining the knowledge of molecular tumor signatures with a better understanding of SIRT3 biological function, regulation and the availability of SIRT3-specific compounds will allow evaluation of SIRT3 as therapeutic tumor target in future studies. Created with

In addition to increasing our understanding of tumor modalities that favor SIRT3 modulation, more work is needed to understand the function and regulation of SIRT3. For example, there is still debate as to whether SIRT3 is regulated by NAD+ content, the NAD+/NA ratio or rather the NAD/NADH redox ratio (119). Given that SIRT3 is mostly located in the mitochondria, cytoplasmic and mitochondrial redox state might have differential effects on SIRT3. NADH imaging allows for assessing the redox state with subcellular resolution (157,158) and future studies combining this powerful technology with SIRT3 expression and activity promise crucial insights into SIRT3 regulation.  This is especially important given the current limitation on SIRT3 activators. Most evidence is related to usage of nonspecific drugs, such as NAD+ boosting compounds, whose effects are only partially mediated through SIRT3. A better understanding of SIRT3 regulation could open new approaches for its activation. In addition, development of more specific, synthetic activators and inhibitors is essential to allow for targeted SIRT3 modulation in different tumor settings.

Taken together, SIRT3 demonstrates a high functional relevance in tumor biology but a better understanding of suitable tumor profiles and more specific compounds are necessary to fully evaluate the potential of SIRT3 modulation as a cancer therapeutic.


  • Sirtuins are deacylases involved in epigenetic and posttranslational regulation
  • Sirtuin 3 is a key regulator of mitochondrial function
  • Sirtuin 3 is involved in tumor pathogenesis by regulating energy metabolism, ROS levels, proliferation and apoptosis
  • Sirtuin 3 can act as tumor suppressor or oncogene dependent on the tumor
  • Sirtuin 3 is a promising therapeutic target in personalized tumor therapy upon development of more specific activators and inhibitors.


No conflicts of interest, financial or otherwise, are declared by the authors.


The authors thank Dr. Douglas C. Wallace for his supervision and support in writing this review. We further thank Dr. Ryan Morrow and Arrienne Butic for proofreading the manuscript and providing constructive feedback.


This work was supported by the German Research Foundation (SCHA 2182/1-1).


1. Mattiuzzi C, Lippi G. Current Cancer Epidemiology. J Epidemiol Glob Health. 2019;9(4):217-22. PMid:31854162 PMCid:PMC7310786

2. Henley SJ, Ward EM, Scott S, Ma J, Anderson RN, Firth AU, et al. Annual report to the nation on the status of cancer, part I: National cancer statistics. Cancer. 2020;126(10):2225-49. PMid:32162336 PMCid:PMC7299151


3. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.


4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74. PMid:21376230


5. DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab. 2020;2(2):127-9.


6. Warburg O, Wind F, Negelein E. THE METABOLISM OF TUMORS IN THE BODY. J Gen Physiol. 1927;8(6):519-30.
PMid:19872213 PMCid:PMC2140820


7. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029-33. PMid:19460998 PMCid:PMC2849637


8. Pavlova NN, Thompson CB. The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016;23(1):27-47.
PMid:26771115 PMCid:PMC4715268


9. Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012;12(10):685-98. PMid:23001348 PMCid:PMC4371788


10. Sies H, Berndt C, Jones DP. Oxidative Stress. Annu Rev Biochem. 2017;86:715-48.


11. Herrmann GK, Russell WK, Garg NJ, Yin YW. Poly(ADP-Ribose) polymerase 1 regulates mitochondrial DNA repair in a metabolism-dependent manner. J Biol Chem. 2021:100309. PMid:33482196 PMCid:PMC7949115


12. Quinn WJ, Jiao J, TeSlaa T, Stadanlick J, Wang Z, Wang L, et al. Lactate Limits T Cell Proliferation via the NAD(H) Redox State. Cell Rep. 2020;33(11):108500. PMid:33326785 PMCid:PMC7830708


13. Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 2011;333(6046):1109-12. PMid:21868666 PMCid:PMC3405151


14. Breda CNS, Davanzo GG, Basso PJ, Saraiva Câmara NO, Moraes-Vieira PMM. Mitochondria as central hub of the immune system. Redox Biol. 2019;26:101255. PMid:31247505 PMCid:PMC6598836


15. Klein K, He K, Younes AI, Barsoumian HB, Chen D, Ozgen T, et al. Role of Mitochondria in Cancer Immune Evasion and Potential Therapeutic Approaches. Front Immunol. 2020;11:573326. PMid:33178201 PMCid:PMC7596324


16. Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020;21(2):85-100. PMid:31636403


17. Matsuura K, Canfield K, Feng W, Kurokawa M. Metabolic Regulation of Apoptosis in Cancer. Int Rev Cell Mol Biol. 2016;327:43-87. PMid:27692180 PMCid:PMC5819894


18. Plati J, Bucur O, Khosravi-Far R. Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities. J Cell Biochem. 2008;104(4):1124-49. PMid:18459149 PMCid:PMC2941905


19. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000;289(5487):2126-8. PMid:11000115


20. Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001;410(6825):227-30. PMid:11242085


21. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403(6771):795-800. PMid:10693811


22. van de Ven RAH, Santos D, Haigis MC. Mitochondrial Sirtuins and Molecular Mechanisms of Aging. Trends Mol Med. 2017;23(4):320-31. PMid:28285806 PMCid:PMC5713479


23. Chang AR, Ferrer CM, Mostoslavsky R. SIRT6, a Mammalian Deacylase with Multitasking Abilities. Physiol Rev. 2020;100(1):145-69. PMid:31437090 PMCid:PMC7002868 


24. Aravind L, Zhang D, de Souza RF, Anand S, Iyer LM. The natural history of ADP-ribosyltransferases and the ADP-ribosylation system. Curr Top Microbiol Immunol. 2015;384:3-32. PMid:25027823 PMCid:PMC6126934


25. Rossmann MG, Moras D, Olsen KW. Chemical and biological evolution of nucleotide-binding protein. Nature. 1974;250(463):194-9. PMid:4368490


26. Sanders BD, Jackson B, Marmorstein R. Structural basis for sirtuin function: what we know and what we don't. Biochim Biophys Acta. 2010;1804(8):1604-16. PMid:19766737 PMCid:PMC2886166


27. Schwer B, North BJ, Frye RA, Ott M, Verdin E. The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol. 2002;158(4):647-57. PMid:12186850 PMCid:PMC2174009


28. Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab. 2014;25(3):138-45.
PMid:24388149 PMCid:PMC3943707


29. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004;303(5666):2011-5. PMid:14976264 


30. Kobayashi Y, Furukawa-Hibi Y, Chen C, Horio Y, Isobe K, Ikeda K, et al. SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. Int J Mol Med. 2005;16(2):237-43. PMid:16012755 


31. Vachharajani VT, Liu T, Brown CM, Wang X, Buechler NL, Wells JD, et al. SIRT1 inhibition during the hypoinflammatory phenotype of sepsis enhances immunity and improves outcome. J Leukoc Biol. 2014;96(5):785-96. PMid:25001863 PMCid:PMC4197566


32. Vachharajani VT, Liu T, Wang X, Hoth JJ, Yoza BK, McCall CE. Sirtuins Link Inflammation and Metabolism. J Immunol Res. 2016;2016:8167273. PMid:26904696 PMCid:PMC4745579


33. Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006;124(2):315-29. PMid:16439206


34. Lagunas-Rangel FA. Current role of mammalian sirtuins in DNA repair. DNA Repair (Amst). 2019;80:85-92.


35. Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature. 2012;483(7388):218-21. PMid:22367546


36. Banks AS, Kon N, Knight C, Matsumoto M, Gutiérrez-Juárez R, Rossetti L, et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 2008;8(4):333-41. PMid:18840364 PMCid:PMC3222897


37. Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007;450(7170):712-6. PMid:18046409 PMCid:PMC2753457 


38. Matsushima S, Sadoshima J. The role of sirtuins in cardiac disease. Am J Physiol Heart Circ Physiol. 2015;309(9):H1375-89. PMid:26232232 PMCid:PMC4666968


39. Oka S, Alcendor R, Zhai P, Park JY, Shao D, Cho J, et al. PPARα-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. Cell Metab. 2011;14(5):598-611. PMid:22055503 PMCid:PMC3217210


40. Winnik S, Auwerx J, Sinclair DA, Matter CM. Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur Heart J. 2015;36(48):3404-12. PMid:26112889 PMCid:PMC4685177


41. Buck E, Bayer H, Lindenberg KS, Hanselmann J, Pasquarelli N, Ludolph AC, et al. Comparison of Sirtuin 3 Levels in ALS and Huntington's Disease-Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models. Front Mol Neurosci. 2017;10:156.
PMid:28603486 PMCid:PMC5445120


42. Lautrup S, Sinclair DA, Mattson MP, Fang EF. NAD. Cell Metab. 2019;30(4):630-55. PMid:31577933 PMCid:PMC6787556


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


44. Roth M, Chen WY. Sorting out functions of sirtuins in cancer. Oncogene. 2014;33(13):1609-20. PMid:23604120 PMCid:PMC4295628


45. Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010;17(1):41-52.
PMid:20129246 PMCid:PMC3711519


46. Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell. 2011;20(4):487-99. PMid:22014574 PMCid:PMC3199577


47. Sebastián C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 2012;151(6):1185-99. PMid:23217706 PMCid:PMC3526953


48. Boily G, He XH, Pearce B, Jardine K, McBurney MW. SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol. Oncogene. 2009;28(32):2882-93. PMid:19503100


49. Xiong Y, Wang M, Zhao J, Han Y, Jia L. Sirtuin 3: A Janus face in cancer (Review). Int J Oncol. 2016;49(6):2227-35.


50. Jung-Hynes B, Nihal M, Zhong W, Ahmad N. Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? J Biol Chem. 2009;284(6):3823-32. PMid:19075016 PMCid:PMC2635052


51. Alhazzazi TY, Kamarajan P, Joo N, Huang JY, Verdin E, D'Silva NJ, et al. Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer. 2011;117(8):1670-8. PMid:21472714 PMCid:PMC3117020


52. Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol. 2007;27(24):8807-14. PMid:17923681 PMCid:PMC2169418


53. Hebert AS, Dittenhafer-Reed KE, Yu W, Bailey DJ, Selen ES, Boersma MD, et al. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol Cell. 2013;49(1):186-99. PMid:23201123 PMCid:PMC3704155


54. Jin L, Galonek H, Israelian K, Choy W, Morrison M, Xia Y, et al. Biochemical characterization, localization, and tissue distribution of the longer form of mouse SIRT3. Protein Sci. 2009;18(3):514-25. PMid:19241369 PMCid:PMC2760358


55. Cooper HM, Spelbrink JN. The human SIRT3 protein deacetylase is exclusively mitochondrial. Biochem J. 2008;411(2):279-85. PMid:18215119


56. Scher MB, Vaquero A, Reinberg D. SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev. 2007;21(8):920-8. PMid:17437997 PMCid:PMC1847710


57. Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. 2010;464(7285):121-5. PMid:20203611 PMCid:PMC2841477


58. Marcus JM, Andrabi SA. SIRT3 Regulation Under Cellular Stress: Making Sense of the Ups and Downs. Front Neurosci. 2018;12:799. PMid:30450031 PMCid:PMC6224517


59. Satterstrom FK, Swindell WR, Laurent G, Vyas S, Bulyk ML, Haigis MC. Nuclear respiratory factor 2 induces SIRT3 expression. Aging Cell. 2015;14(5):818-25. PMid:26109058 PMCid:PMC4568969


60. Yoon SP, Kim J. Poly(ADP-ribose) polymerase 1 contributes to oxidative stress through downregulation of sirtuin 3 during cisplatin nephrotoxicity. Anat Cell Biol. 2016;49(3):165-76. PMid:27722009 PMCid:PMC5052225


61. Hirschey MD, Shimazu T, Jing E, Grueter CA, Collins AM, Aouizerat B, et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell. 2011;44(2):177-90. PMid:21856199 PMCid:PMC3563434


62. Cantó C, Sauve AA, Bai P. Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes. Mol Aspects Med. 2013;34(6):1168-201. PMid:23357756 PMCid:PMC3676863


63. Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP. SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc Natl Acad Sci U S A. 2002;99(21):13653-8. PMid:12374852 PMCid:PMC129731


64. Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem. 2002;277(47):45099-107. PMid:12297502


65. Madsen AS, Andersen C, Daoud M, Anderson KA, Laursen JS, Chakladar S, et al. Investigating the Sensitivity of NAD+-dependent Sirtuin Deacylation Activities to NADH. J Biol Chem. 2016;291(13):7128-41. PMid:26861872 PMCid:PMC4807294


66. Gambini J, Gomez-Cabrera MC, Borras C, Valles SL, Lopez-Grueso R, Martinez-Bello VE, et al. Free [NADH]/[NAD(+)] regulates sirtuin expression. Arch Biochem Biophys. 2011;512(1):24-9. PMid:21575591


67. Shan C, Kang HB, Elf S, Xie J, Gu TL, Aguiar M, et al. Tyr-94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth. J Biol Chem. 2014;289(31):21413-22. PMid:24962578 PMCid:PMC4118105


68. Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell. 2010;143(5):802-12. PMid:21094524 PMCid:PMC3018849


69. Hallows WC, Lee S, Denu JM. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci U S A. 2006;103(27):10230-5. PMid:16790548 PMCid:PMC1480596


70. Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A. 2008;105(38):14447-52. PMid:18794531 PMCid:PMC2567183


71. Cimen H, Han MJ, Yang Y, Tong Q, Koc H, Koc EC. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry. 2010;49(2):304-11. PMid:20000467 PMCid:PMC2826167


72. Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, et al. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab. 2010;12(6):654-61. PMid:21109197 PMCid:PMC3310379


73. Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C. Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol. 2008;382(3):790-801. PMid:18680753


74. Hallows WC, Yu W, Smith BC, Devries MK, Devires MK, Ellinger JJ, et al. Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell. 2011;41(2):139-49. PMid:21255725 PMCid:PMC3101115


75. 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:e601. PMid:23598413 PMCid:PMC3641353


76. Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell. 2010;40(6):893-904. PMid:21172655 PMCid:PMC3266626


77. Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest. 2009;119(9):2758-71. PMid:19652361 PMCid:PMC2735933


78. Yang H, Zhou L, Shi Q, Zhao Y, Lin H, Zhang M, et al. SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth. EMBO J. 2015;34(8):1110-25. PMid:25755250 PMCid:PMC4406655


79. Xiong Y, Wang L, Wang S, Wang M, Zhao J, Zhang Z, et al. SIRT3 deacetylates and promotes degradation of P53 in PTEN-defective non-small cell lung cancer. J Cancer Res Clin Oncol. 2018;144(2):189-98. PMid:29103158


80. Cheng Y, Ren X, Gowda AS, Shan Y, Zhang L, Yuan YS, et al. Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress. Cell Death Dis. 2013;4:e731. PMid:23868064 PMCid:PMC3730425


81. Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB, Gupta MP. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol. 2008;28(20):6384-401. PMid:18710944 PMCid:PMC2577434


82. Hafner AV, Dai J, Gomes AP, Xiao CY, Palmeira CM, Rosenzweig A, et al. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY). 2010;2(12):914-23. PMid:21212461 PMCid:PMC3034180


83. Pedersen PL. Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr. 2007;39(3):211-22. PMid:17879147


84. Dalmonte ME, Forte E, Genova ML, Giuffrè A, Sarti P, Lenaz G. Control of respiration by cytochrome c oxidase in intact cells: role of the membrane potential. J Biol Chem. 2009;284(47):32331-5. PMid:19776013 PMCid:PMC2781647


85. Zhao W, Wang J, Varghese M, Ho L, Mazzola P, Haroutunian V, et al. Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects. Neuropsychiatr Dis Treat. 2015;11:565-74. PMid:25784811 PMCid:PMC4356684


86. Shen L, Sun X, Fu Z, Yang G, Li J, Yao L. The fundamental role of the p53 pathway in tumor metabolism and its implication in tumor therapy. Clin Cancer Res. 2012;18(6):1561-7. PMid:22307140


87. Xu L, Li Y, Zhou L, Dorfman RG, Liu L, Cai R, et al. SIRT3 elicited an anti-Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis. Cancer Med. 2019;8(5):2380-91. PMid:30993888 PMCid:PMC6536927


88. Bell EL, Emerling BM, Ricoult SJ, Guarente L. SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene. 2011;30(26):2986-96. PMid:21358671 PMCid:PMC3134877


89. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721-32. PMid:13130303


90. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294(5545):1337-40. PMid:11598268


91. Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell. 2011;19(3):416-28. PMid:21397863 PMCid:PMC3065720


92. Quan Y, Wang N, Chen Q, Xu J, Cheng W, Di M, et al. SIRT3 inhibits prostate cancer by destabilizing oncoprotein c-MYC through regulation of the PI3K/Akt pathway. Oncotarget. 2015;6(28):26494-507. PMid:26317998 PMCid:PMC4694917


93. Inuzuka H, Gao D, Finley LW, Yang W, Wan L, Fukushima H, et al. Acetylation-dependent regulation of Skp2 function. Cell. 2012;150(1):179-93. PMid:22770219 PMCid:PMC3595190 


94. 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. PMid:28878358 PMCid:PMC5587591


95. Lee JJ, van de Ven RAH, Zaganjor E, Ng MR, Barakat A, Demmers JJPG, et al. Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3. Proc Natl Acad Sci U S A. 2018;115(27):7057-62. PMid:29915029 PMCid:PMC6142214


96. Dong XC, Jing LM, Wang WX, Gao YX. Down-regulation of SIRT3 promotes ovarian carcinoma metastasis. Biochem Biophys Res Commun. 2016;475(3):245-50. PMid:27216459


97. Li R, Quan Y, Xia W. SIRT3 inhibits prostate cancer metastasis through regulation of FOXO3A by suppressing Wnt/β-catenin pathway. Exp Cell Res. 2018;364(2):143-51. PMid:29421536


98. Zeng X, Wang N, Zhai H, Wang R, Wu J, Pu W. SIRT3 functions as a tumor suppressor in hepatocellular carcinoma. Tumour Biol. 2017;39(3):1010428317691178. PMid:28347248


99. Huang S, Guo H, Cao Y, Xiong J. MiR-708-5p inhibits the progression of pancreatic ductal adenocarcinoma by targeting Sirt3. Pathol Res Pract. 2019;215(4):794-800. PMid:30683474


100. Liu Y, Liu YL, Cheng W, Yin XM, Jiang B. The expression of SIRT3 in primary hepatocellular carcinoma and the mechanism of its tumor suppressing effects. Eur Rev Med Pharmacol Sci. 2017;21(5):978-98. 


101. Song CL, Tang H, Ran LK, Ko BC, Zhang ZZ, Chen X, et al. Sirtuin 3 inhibits hepatocellular carcinoma growth through the glycogen synthase kinase-3β/BCL2-associated X protein-dependent apoptotic pathway. Oncogene. 2016;35(5):631-41. PMid:25915842


102. Allison SJ, Milner J. SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. Cell Cycle. 2007;6(21):2669-77. PMid:17957139


103. Xiao K, Jiang J, Wang W, Cao S, Zhu L, Zeng H, et al. Sirt3 is a tumor suppressor in lung adenocarcinoma cells. Oncol Rep. 2013;30(3):1323-8. PMid:23842789


104. Tang X, Li Y, Liu L, Guo R, Zhang P, Zhang Y, et al. Sirtuin 3 induces apoptosis and necroptosis by regulating mutant p53 expression in small‑cell lung cancer. Oncol Rep. 2020;43(2):591-600.


105. Wu Y, Gao WN, Xue YN, Zhang LC, Zhang JJ, Lu SY, et al. SIRT3 aggravates metformin-induced energy stress and apoptosis in ovarian cancer cells. Exp Cell Res. 2018;367(2):137-49. PMid:29580688


106. Xiong Y, Wang M, Zhao J, Wang L, Li X, Zhang Z, et al. SIRT3 is correlated with the malignancy of non-small cell lung cancer. Int J Oncol. 2017;50(3):903-10. PMid:28197634


107. Cui Y, Qin L, Wu J, Qu X, Hou C, Sun W, et al. SIRT3 Enhances Glycolysis and Proliferation in SIRT3-Expressing Gastric Cancer Cells. PLoS One. 2015;10(6):e0129834. PMid:26121691 PMCid:PMC4487898


108. Baccelli I, Gareau Y, Lehnertz B, Gingras S, Spinella JF, Corneau S, et al. Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia. Cancer Cell. 2019;36(1):84-99.e8. PMid:31287994


109. Li M, Chiang YL, Lyssiotis CA, Teater MR, Hong JY, Shen H, et al. Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis. Cancer Cell. 2019;35(6):916-31.e9. PMid:31185214 PMCid:PMC7534582


110. Bergaggio E, Riganti C, Garaffo G, Vitale N, Mereu E, Bandini C, et al. IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. Blood. 2019;133(2):156-67. PMid:30455381 


111. Li H, Feng Z, Wu W, Li J, Zhang J, Xia T. SIRT3 regulates cell proliferation and apoptosis related to energy metabolism in non-small cell lung cancer cells through deacetylation of NMNAT2. Int J Oncol. 2013;43(5):1420-30. PMid:24042441 PMCid:PMC3823398


112. Chen S, Yang X, Yu M, Wang Z, Liu B, Liu M, et al. SIRT3 regulates cancer cell proliferation through deacetylation of PYCR1 in proline metabolism. Neoplasia. 2019;21(7):665-75. PMid:31108370 PMCid:PMC6526305


113. Wei Z, Song J, Wang G, Cui X, Zheng J, Tang Y, et al. Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis. Nat Commun. 2018;9(1):4468. PMid:30367038 PMCid:PMC6203763


114. Wang Y, Sun X, Ji K, Du L, Xu C, He N, et al. Sirt3-mediated mitochondrial fission regulates the colorectal cancer stress response by modulating the Akt/PTEN signalling pathway. Biomed Pharmacother. 2018;105:1172-82. PMid:30021354


115. Xu LX, Hao LJ, Ma JQ, Liu JK, Hasim A. SIRT3 promotes the invasion and metastasis of cervical cancer cells by regulating fatty acid synthase. Mol Cell Biochem. 2020;464(1-2):11-20. PMid:31677030


116. Kamarajan P, Alhazzazi TY, Danciu T, D'silva NJ, Verdin E, Kapila YL. Receptor-interacting protein (RIP) and Sirtuin-3 (SIRT3) are on opposite sides of anoikis and tumorigenesis. Cancer. 2012;118(23):5800-10. PMid:22674009 PMCid:PMC3443499


117. Sengupta A, Haldar D. Human sirtuin 3 (SIRT3) deacetylates histone H3 lysine 56 to promote nonhomologous end joining repair. DNA Repair (Amst). 2018;61:1-16. PMid:29136592


118. Carafa V, Rotili D, Forgione M, Cuomo F, Serretiello E, Hailu GS, et al. Sirtuin functions and modulation: from chemistry to the clinic. Clin Epigenetics. 2016;8:61. PMid:27226812 PMCid:PMC4879741


119. 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. PMid:32724473 PMCid:PMC7381741


120. Rajman L, Chwalek K, Sinclair DA. Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metab. 2018;27(3):529-47. PMid:29514064 PMCid:PMC6342515


121. Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, LeBoeuf SE, Gay LJ, et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest. 2013;123(3):1068-81. PMid:23426180 PMCid:PMC3582128


122. 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;6:6656. PMid:25871545 PMCid:PMC4441304


123. Arora S, Singh S, Piazza GA, Contreras CM, Panyam J, Singh AP. Honokiol: a novel natural agent for cancer prevention and therapy. Curr Mol Med. 2012;12(10):1244-52. PMid:22834827 PMCid:PMC3663139


124. Xu HL, Tang W, Du GH, Kokudo N. Targeting apoptosis pathways in cancer with magnolol and honokiol, bioactive constituents of the bark of Magnolia officinalis. Drug Discov Ther. 2011;5(5):202-10. PMid:22466367


125. Arora S, Bhardwaj A, Srivastava SK, Singh S, McClellan S, Wang B, et al. Honokiol arrests cell cycle, induces apoptosis, and potentiates the cytotoxic effect of gemcitabine in human pancreatic cancer cells. PLoS One. 2011;6(6):e21573. PMid:21720559 PMCid:PMC3123370


126. 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. PMid:28423723 PMCid:PMC5470953


127. Tian W, Deng Y, Li L, He H, Sun J, Xu D. Honokiol synergizes chemotherapy drugs in multidrug resistant breast cancer cells via enhanced apoptosis and additional programmed necrotic death. Int J Oncol. 2013;42(2):721-32. PMid:23242346


128. Huang K, Chen Y, Zhang R, Wu Y, Ma Y, Fang X, et al. Honokiol induces apoptosis and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells in vitro and in vivo. Cell Death Dis. 2018;9(2):157. PMid:29410403 PMCid:PMC5833587


129. 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. PMid:28424621 PMCid:PMC5380914


130. Loguercio C, Festi D. Silybin and the liver: from basic research to clinical practice. World J Gastroenterol. 2011;17(18):2288-301. PMid:21633595 PMCid:PMC3098397


131. Kaur M, Velmurugan B, Tyagi A, Deep G, Katiyar S, Agarwal C, et al. Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft. Mol Cancer Ther. 2009;8(8):2366-74. PMid:19638451 PMCid:PMC2728169


132. Flaig TW, Glodé M, Gustafson D, van Bokhoven A, Tao Y, Wilson S, et al. A study of high-dose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer. Prostate. 2010;70(8):848-55. PMid:20127732


133. Gertz M, Nguyen GT, Fischer F, Suenkel B, Schlicker C, Fränzel B, et al. A molecular mechanism for direct sirtuin activation by resveratrol. PLoS One. 2012;7(11):e49761. PMid:23185430 PMCid:PMC3504108


134. Pan W, Yu H, Huang S, Zhu P. Resveratrol Protects against TNF-α-Induced Injury in Human Umbilical Endothelial Cells through Promoting Sirtuin-1-Induced Repression of NF-KB and p38 MAPK. PLoS One. 2016;11(1):e0147034. PMid:26799794 PMCid:PMC4723256


135. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425(6954):191-6. PMid:12939617


136. Kershaw J, Kim KH. The Therapeutic Potential of Piceatannol, a Natural Stilbene, in Metabolic Diseases: A Review. J Med Food. 2017;20(5):427-38. PMid:28387565 PMCid:PMC5444415


137. Bagul PK, Katare PB, Bugga P, Dinda AK, Banerjee SK. SIRT-3 Modulation by Resveratrol Improves Mitochondrial Oxidative Phosphorylation in Diabetic Heart through Deacetylation of TFAM. Cells. 2018;7(12). PMid:30487434 PMCid:PMC6315986


138. 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:e1576. PMid:25522270 PMCid:PMC4454164


139. Guan X, Lin P, Knoll E, Chakrabarti R. Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies. PLoS One. 2014;9(9):e107729. PMid:25221980 PMCid:PMC4164625


140. Nikas IP, Paschou SA, Ryu HS. The Role of Nicotinamide in Cancer Chemoprevention and Therapy. Biomolecules. 2020;10(3). PMid:32245130 PMCid:PMC7175378


141. Galli U, Mesenzani O, Coppo C, Sorba G, Canonico PL, Tron GC, et al. Identification of a sirtuin 3 inhibitor that displays selectivity over sirtuin 1 and 2. Eur J Med Chem. 2012;55:58-66. PMid:22835719


142. Chen G, Zhang B, Xu H, Sun Y, Shi Y, Luo Y, et al. Suppression of Sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775-induced DNA damage and apoptosis. Oncogene. 2017;36(50):6863-72. PMid:28869605


143. Broussy S, Laaroussi H, Vidal M. Biochemical mechanism and biological effects of the inhibition of silent information regulator 1 (SIRT1) by EX-527 (SEN0014196 or selisistat). J Enzyme Inhib Med Chem. 2020;35(1):1124-36. PMid:32366137 PMCid:PMC7241506 


144. Süssmuth SD, Haider S, Landwehrmeyer GB, Farmer R, Frost C, Tripepi G, et al. An exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington's disease. Br J Clin Pharmacol. 2015;79(3):465-76. PMid:25223731 PMCid:PMC4345957


145. Nguyen GT, Gertz M, Steegborn C. Crystal structures of Sirt3 complexes with 4'-bromo-resveratrol reveal binding sites and inhibition mechanism. Chem Biol. 2013;20(11):1375-85. PMid:24211137


146. George J, Nihal M, Singh CK, Ahmad N. 4'-Bromo-resveratrol, a dual Sirtuin-1 and Sirtuin-3 inhibitor, inhibits melanoma cell growth through mitochondrial metabolic reprogramming. Mol Carcinog. 2019;58(10):1876-85. PMid:31292999 PMCid:PMC6721992


147. Karaman B, Sippl W. Docking and binding free energy calculations of sirtuin inhibitors. Eur J Med Chem. 2015;93:584-98. PMid:25748123


148. Patel K, Sherrill J, Mrksich M, Scholle MD. Discovery of SIRT3 Inhibitors Using SAMDI Mass Spectrometry. J Biomol Screen. 2015;20(7):842-8. PMid:26024947


149. Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell. 2008;13(5):454-63. PMid:18455128 PMCid:PMC2742717


150. Hirai S, Endo S, Saito R, Hirose M, Ueno T, Suzuki H, et al. Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation. PLoS One. 2014;9(7):e102831. PMid:25033286 PMCid:PMC4102575


151. Rousalova I, Banerjee S, Sangwan V, Evenson K, McCauley JA, Kratzke R, et al. Minnelide: a novel therapeutic that promotes apoptosis in non-small cell lung carcinoma in vivo. PLoS One. 2013;8(10):e77411. PMid:24143232 PMCid:PMC3797124


152. Kumar A, Corey C, Scott I, Shiva S, D'Cunha J. Minnelide/Triptolide Impairs Mitochondrial Function by Regulating SIRT3 in P53-Dependent Manner in Non-Small Cell Lung Cancer. PLoS One. 2016;11(8):e0160783. PMid:27501149 PMCid:PMC4976872


153. 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 Genomics Proteomics. 2018;15(1):73-89. PMCid:PMC5822178


154. Disch JS, Evindar G, Chiu CH, Blum CA, Dai H, Jin L, et al. Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3. J Med Chem. 2013;56(9):3666-79. PMid:23570514


155. Zhou Y, Li C, Peng J, Xie L, Meng L, Li Q, et al. DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery. J Am Chem Soc. 2018;140(46):15859-67. PMid:30412395


156. Ma J, Liu B, Yu D, Zuo Y, Cai R, Yang J, et al. SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation. Br J Haematol. 2019;187(1):49-64. PMid:31236919 PMCid:PMC6790595


157. Schaefer PM, Hilpert D, Niederschweiberer M, Neuhauser L, Kalinina S, Calzia E, et al. Mitochondrial matrix pH as a decisive factor in neurometabolic imaging. Neurophotonics. 2017;4(4):045004. PMid:29181426 PMCid:PMC5685807


158. Schaefer PM, Kalinina S, Rueck A, von Arnim CAF, von Einem B. NADH Autofluorescence-A Marker on its Way to Boost Bioenergetic Research. Cytometry A. 2018 PMid:30211978