2.1. SIRT2 Regulates Replication, Transcription, and Translation

At the replication level, on the one hand, after DNA damage, SIRT2 mainly recovers DNA replication from the stress state through ataxia telangiectasia-mutated and Rad3-related (ATR) kinase checkpoint. At sites of DNA damage, SIRT2 can deacetylate ATR-interacting protein (ATRIP) K32, thereby driving ATR activation through the binding of ATR-ATRIP to replication protein A-coated single-stranded DNA (RPA-ssDNA). Furthermore, SIRT2 can deacetylate CDK9 lysine 48 and partially depend on ATR to activate CDK9 kinase activity, promoting the recovery of DNA replication [Reference Zhang, Head and Daddacha9, Reference Zhang, Park and Pantazides10]. On the other hand, SIRT2 maintains the activity of RNR by deacetylating the subunit RRM2 of ribonucleotide reductase (RNR), ensuring a sufficient supply of precursor dNTPs for DNA synthesis and promoting the progress of DNA replication [Reference Chen, Luo and Warncke11].

At the transcriptional level, SIRT2 inhibits transcription through its deacetylation activity. In the transcription system of mouse cellular RNA polymerase I (Pol I), SIRT2 can deacetylate the TATA box-binding protein (TBP) factor TIF-IB/SL1 TAF_I68 and impair the binding of TAFI68 to rDNA promoters, resulting in rDNA transcription inhibition [Reference Muth, Nadaud, Grummt and Voit12]. In addition, the interaction between SIRT 2 and the homeobox transcription factor HOXA10 was identified in human cells [Reference Bae, Swanson, Vassilev and Howard13].

At the translational level, the most studied SIRT2 is eukaryotic translation initiation factor 5A (eIF5A). SIRT2 can regulate the subcellular localization of eIF5A by regulating the acetylation level of eIF5A. The acetylated form of eIF5A is located in the nucleus, while unacetylated eIF5A is located in the cytoplasm, which enables it to perform different functions in different cell sites, and its specific functional mechanism remains to be studied [Reference Shah, Ito, Nakata and Yoshida14–Reference Ishfaq, Maeta, Maeda, Natsume, Ito and Yoshida16].

2.2. SIRT2 Is Involved in Epigenetic and Post-Translational Modifications

After DNA replication, transcription, and translation, the synthesized protein is an inactive protein precursor that needs to undergo various post-translational modifications to become a protein with specific biological functions. Studies have shown that SIRT2 can participate in the epigenetic regulation of genes by the post-translational modification of histones, thereby indirectly regulating life activities within cells. SIRT2 can also directly participate in regulating intracellular life activities through the post-translational modification of nonhistone proteins. The details are shown in Table 1.

TABLE 1: Posttranslational modifications involving SIRT2.

In summary, SIRT2 can lead to biologically active proteins through replication, transcription, translation, and epigenetic and post-translational modifications related to gene expression. This finding is consistent with Li et al.’s research, which showed that SIRT2 can target genes and proteins involved in the regulation of gene expression and metabolism and can target certain diseases [Reference Li, Valsakumar, Poorey, Bekiranov and Smith31, Reference Zhang, Dammer, Duong, Danelia, Seyfried and Yu32]. This finding suggests that SIRT2 can form crosstalk between gene expression regulation and metabolism and participate in the pathological process of disease.

3.1. SIRT2 and Lipid Metabolism-Related Signal Transduction

Lipid metabolism includes lipid uptake, synthesis, oxidation, and storage. The key regulatory factors include insulin, glucagon, and adrenaline. Insulin promotes the synthesis of triglycerides in the liver and the storage of triglycerides in white adipose tissue (WAT). Glucagon and adrenaline stimulate the fat decomposition in WAT and fatty acid oxidation in other tissues when nutrients are limited (Figure 1).

FIGURE 1: SIRT2 is involved in lipid metabolism. SIRT2 affects lipid synthesis through ACLY. P300/PCAF can stabilize ACLY by acetylation, thereby promoting lipid synthesis. SIRT2 degrades ACLY by deacetylation to inhibit lipid synthesis. SIRT2 promotes the binding of SREBP-2 to the SRE by promoting the nuclear translocation of SREBP-2, thereby promoting the transcription of cholesterol synthesis-related genes and ultimately promoting the synthesis of cholesterol. SIRT2 inhibits lipid synthesis by deacetylating HNF4α. SIRT2 promotes fatty acid oxidation and inhibits lipid synthesis by inhibiting the nuclear translocation of FOXO1. In addition, SIRT2 promotes fatty acid oxidation through the deacetylation of PGC-1.

3.2. Fatty Acid Oxidation

Fatty acid oxidation is the main source of energy in the body and mainly occurs in the liver and muscle but does not occur in nerve tissue. β-oxidation and specific oxidation modes (propionic acid oxidation, α-oxidation, ω-oxidation, and unsaturated fatty acid oxidation) occur.

Recent studies have shown that genes involved in fatty acid oxidation are transcriptionally regulated by PPAR and its coactivator peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1). PPARα can enhance fatty acid β-oxidation and the expression of ketogenic genes, and PPARδ can induce long-chain fatty acid (LCFA) oxidation genes and control mitochondrial biogenesis and function by inducing PGC-1, thereby affecting the oxidation of fatty acids [Reference Nakamura, Yudell and Loor51].

Previous studies have shown that SIRT2 is involved in lipid synthesis by affecting the nuclear translocation of FOXO1, which inhibits the transcription of PPARγ [Reference Wang and Tong39]. SIRT2 can also inhibit lipid synthesis by downregulating FOXO1 [Reference Park, Chung, Son, Yun, Park, Yim, Jung, Lee and Jeong52]. However, a recent study by Akbulut et al. showed that decreased FOXO1 levels were related to lipid peroxidation and increased SIRT2 expression levels [Reference Akbulut, Aktas and Akbulut53]. However, the specific mechanism remains unclear. In addition, Krishnan et al. showed that SIRT2 could deacetylate PGC-1, resulting in increased β-oxidation and mitochondrial gene expression [Reference Krishnan, Danzer, Simka, Ukropec, Walter, Kumpf, Mirtschink, Ukropcova, Gasperikova, Pedrazzini and Krek54].

3.3. SIRT2 and Glucose Metabolism-Related Signal Transduction

The metabolism of sugar in the human body is divided into anabolism and catabolism, which are in a dynamic balance to stabilize the blood sugar levels. The main processes of glucose metabolism in the human body include the uptake of glucose by intestinal epithelial cells, the decomposition of glycogen in the liver, gluconeogenesis to produce glucose, and the uptake and decomposition of blood glucose by other tissues (Figure 2).

FIGURE 2: SIRT2 is involved in glucose metabolism. SIRT2 promotes gluconeogenesis by deacetylating FOXO1 and PEPCK. SIRT2 can promote glycolysis by interacting with glycolytic enzymes. SIRT2 can promote insulin secretion through the Akt/GSK-3β/β-catenin pathway. SIRT2 can also regulate glucose metabolism through the insulin-PI3K-AKT-metabolism pathway. AMPK can phosphorylate and activate SIRT2 and enhance the interaction between SIRT2 and AKT. In addition, SIRT2 can activate AKT and PDK1 through deacetylation, thereby promoting glycolysis and inhibiting gluconeogenesis.

4.1. Inflammation

Research has shown that there is a close relationship between metabolism and immunity [Reference Osborn and Olefsky75]. Systemic low-grade chronic inflammation plays a key role in the pathogenesis of metabolic disorders, and the main regulators are nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and the inflammasome (NOD-like receptor pyrin domain-containing 3, NLRP3).

In the NF-κB pathway, SIRT2 is inactivated by Lys 310 deacetylation of the NF-κB subunit p65 in the cytoplasm, which decreases the expression of its downstream target genes (interleukin-1β (IL-1β), IL-6, monocyte chemoattractant protein 1 (MCP-1), a chemokine that regulates the expression and secretion of activated normal T cells (RANTES), matrix metalloproteinase 9 (MMP-9), and MMP-13), thereby exerting anti-inflammatory effects [Reference Rothgiesser, Erener, Waibel, Luscher and Hottiger76, Reference Lin, Sun, Jiang, Hong and Zheng77]. Lee et al. showed that inhibiting SIRT2 could reduce the phosphorylation and degradation of NF-κB, reduce the phosphorylation of NF-κB subunit p65 Ser 536, reduce the nuclear translocation of p65, and inhibit the expression of NF-κB [Reference Lee, Jung, Kim, Nguyen-Thanh, Kang, Lee, Park and Kim78]. This cascade reduces the expression of iNOS and NO, the downstream target genes of NF-κB, and exerts an anti-inflammatory effect. However, there has been no discussion regarding the specific molecular mechanism linking the phosphorylation and acetylation of p65. In other experimental inflammatory disease models, the anti-inflammatory effect of SIRT2 has been demonstrated by inhibiting the NF-κB signalling pathway [Reference Lee, Jung, Kim, Nguyen-Thanh, Kang, Lee, Park and Kim78–Reference Chen, Wu, Ding and Ying81]. However, Pais et al. showed that SIRT2 also stimulates the activation of NF-κB through Toll-like receptors (TLRs), leading to an inflammatory response [Reference Pais, Szego, Marques, Miller-Fleming, Antas, Guerreiro, de Oliveira, Kasapoglu and Outeiro82]. In addition, studies have shown that the inflammatory NF-κB pathway is associated with SIRT2 and HSP90, but current research related to this topic is still controversial [Reference Thangjam, Birmpas, Barabutis, Gregory, Clemens, Newton, Fulton and Catravas83, Reference Sun, Wang, Fang, Xu, lin, Zhao, Nazarali and Ji84].

In the MAPK-related inflammatory signalling pathway, SIRT2 deacetylates MKP-1, decreasing the acetylation level of MKP-1, which promotes the transduction of TLR signalling, upregulates MAPK signalling, and increases the ERK, p38, and JNK phosphorylation levels, thereby promoting the production of the proinflammatory factors IL-1β, IL-6, TNF-α, and iNOS, leading to the occurrence of inflammation [Reference Eo, Kim, Choi, Kim and Kim85–Reference Jung, Park, Kang and Kim88].

In the NLRP3 inflammatory signalling pathway, NLRP3 is acetylated by macrophages, which promotes the assembly and activation of the NLRP3 inflammasome, thereby enabling the production of the inflammatory cytokines IL-1β and IL-18 to induce inflammatory reactions [Reference He, Chiang, Luo, Zheng, Qiao, Wang, Tan, Ohkubo, Mu, Zhao, Wu and Chen89]. By contrast, the targeted deacetylation of NLRP3 by SIRT2 inactivates this process.

4.2. Oxidative Stress

SIRT2 protects against oxidative damage, and SIRT2-mediated deacetylation of its targets plays an important role during oxidative stress [Reference Gomes, Fleming Outeiro and Cavadas90, Reference Sarikhani, Mishra, Desingu, Kotyada, Wolfgeher, Gupta, Singh and Sundaresan91]. Studies have shown that reactive oxygen species (ROS) are important enzymes that catalyse the generation of oxygen free radicals and activate oxidative stress responses [Reference Mazereeuw, Herrmann, Andreazza, Scola, Ma, Oh and Lanctot92]. SIRT2 can act on ROS through signalling pathways, such as FOXO3, Nrf2, PEPCK1, poly (ADP-ribose) polymerase 1 (PARP1), and p65, to reduce the generation of oxygen free radicals [Reference Wang, Chan, Chen, Guan, Lin and Tong93].

Under oxidative stress, SIRT2 can activate its target FOXO3 through deacetylation, and then, FOXO3a shuttles to the nucleus and induces the expression of its target antioxidants manganese superoxide dismutase (MnSOD), SOD1/2, p27 (Kip1), and Bim, which reduce the cellular ROS levels and enhance the cellular antioxidant capacity [Reference Wang, Nguyen, Qin and Tong94–Reference Yang, Peng, Liu, Zhou, Meng and Yuan96].

Nrf2 is a key transcription factor that regulates the gene expression of multiple antioxidant enzymes [Reference Shi, Zhang, Zhang, Gao, Liu, Chen and Yang97]. Under normal physiological conditions, Nrf2 stably binds Kelch-like enoyl-CoA hydratase-associated protein 1 (Keap1) and is stabilized in the cytoplasm, preventing Nrf2 translocation to the nucleus and inhibiting the ability of Nrf2 to activate target genes [Reference Liu, Ren, Liu, Li, Huang and Yang98]. Under oxidative stress, SIRT2 induces the dissociation of Nrf2 and Keap1, and Nrf2 translocates to the nucleus to interact with antioxidant response elements (AREs), thereby activating the target gene antioxidant element haem oxygenase 1 (HO-1) to protect cells from oxidative damage [Reference Shi, Zhang, Zhang, Gao, Liu, Chen and Yang97–Reference Zhao, Zhang, Tao, Zhang, Sun, Wang and Song100].

In addition, SIRT2 can regulate ROS by targeting metabolic enzymes, such as glucose 6-phosphate dehydrogenase (G6PD), phosphoglyceride mutant enzyme (PGAM2), and NF-κB [Reference Singh, Chhabra, Ndiaye, Garcia-Peterson, Mack and Ahmad101]. Under oxidative stress conditions, SIRT2 can deacetylate and activate the key enzyme G6PD in the pentose phosphate pathway (PPP) to stimulate the production of cytoplasmic NADPH, thereby maintaining the reduced form of GSH against oxidative damage [Reference Kitada, Ogura, Monno and Koya102–Reference de Angelis, Amatore, Checconi, Zevini, Fraternale, Magnani, Hiscott, De Chiara, Palamara and Nencioni104]. In addition, Xu et al. showed that SIRT2 could increase NADPH production through the deacetylation and activation of PGAM2 to enable cells to respond to oxidative stress [Reference Xu, Li, Lv, Li, Zhou, Deng, Guan, Lei and Xiong105]. SIRT2 promotes the activation of enzymes, including NADPH oxidase, xanthine oxidoreductase, inducible NO synthase, cyclooxygenase-2, and cytochrome p450, through the activation of NF-κB. SIRT2 can also target ROS-inhibiting enzymes, such as SOD 1 and 2, thioredoxin, and glutathione S-transferase, which increase the level of ROS in cells. In turn, NF-κB activity is also regulated by the ROS levels [Reference Pais, Szego, Marques, Miller-Fleming, Antas, Guerreiro, de Oliveira, Kasapoglu and Outeiro82, Reference Morgan and Liu106].

Studies have shown that SIRT2 can also deacetylate PARP1 K249, resulting in the ubiquitination and degradation of PARP1 by WW domain-containing protein 2 (WWP2), thereby alleviating the vascular oxidative stress injury caused by PARP1 mediated by angiotensin II (Ang II) [Reference Zhang, Zhang, Wu, Wu, You, Lu, Liu, Huang, Xu, Cao and Sun107]. Alternatively, SIRT2 can deacetylate K431 of Bcl-2-associated athanogene 3 (BAG3), thereby mediating BAG3 binding to PARP1 to promote the ubiquitination degradation of WWP2 at PARP1 K249 to protect against oxidative damage [Reference Zhang, Zhang, Miao, Shi, Chen, Wu, Zou, Ma, You, Lu, Huang, Liu, Xu, Cao and Sun108].

Collectively, these findings suggest that SIRT2 plays a key role in regulating the oxidative stress response, which protects organisms from metabolic damage through oxidative stress-dependent mechanisms.

5.1. SIRT2 and Neurodegenerative Diseases

Neurodegenerative diseases are neurasthenic disorders in which the main pathogenic mechanism is protein degradation and inflammatory defects caused by impairments in energy metabolism and disturbances in redox homeostasis [Reference Lin and Beal109, Reference McWilliams and Ganley110]. SIRT2 is expressed in almost all brain cells, particularly oligodendrocytes in the central nervous system, and is indirectly involved in cellular processes relevant to the pathophysiology of neurodegenerative diseases [Reference Pandithage, Lilischkis, Harting, Wolf, Jedamzik, Lüscher-Firzlaff, Vervoorts, Lasonder, Kremmer, Knöll and Lüscher111, Reference Zhu, Zhao, Wang, Dimova, Liu, Feng and Cambi112].

In Huntington’s disease (HD), SIRT2 inhibition was shown to prevent HD by reducing sterol biosynthesis and exerting neuroprotective effects [Reference Luthi-Carter, Taylor, Pallos, Lambert, Amore, Parker, Moffitt, Smith, Runne, Gokce, Kuhn, Xiang, Maxwell, Reeves, Bates, Neri, Thompson, Marsh and Kazantsev113]. This protective effect was closely related to the transcriptional regulation of genes that control metabolism, including sterol and fatty acid biosynthesis, carbohydrate metabolism, and purine metabolism [Reference de Oliveira, Sarkander, Kazantsev and Outeiro114].

Traumatic brain injury (TBI) is associated with an increased risk of different neurodegenerative diseases, and the main pathological features include neuroinflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction. Studies have shown that SIRT2 plays a protective role in TBI. In TBI, SIRT2 inhibition stimulates NF-κB activation, induces MMP-9 expression, and perturbs the blood-brain barrier (BBB) integrity, allowing plasma components, such as macrophages and inflammatory factors, to more readily cross the BBB, which worsens neuroinflammation [Reference Yuan, Xu, Lu, Nie, Ding, Ying and Tian115]. Alternatively, SIRT2 exerts a protective effect by inhibiting p53-induced ferroptosis [Reference Gao, Li and Song116].

The pathogenesis of acute ischaemic stroke (AIS) mainly involves oxidative stress, impaired mitochondrial function, and poststroke inflammation [Reference Zhang, Yan and Zhang117]. Studies have shown that SIRT2 expression is positively correlated with the severity of AIS and proinflammatory cytokines, but its specific mechanism still needs further study.

5.2. SIRT2 and Cancer

Metabolic pathway reprogramming is a hallmark of cancer, and SIRT2 can affect tumour progression through metabolic pathways. In recent years, the role of SIRT2 in cancer has remained controversial, and SIRT2 acts as both an oncogene and a tumour suppressor; to a certain extent, its impact may be greater than that of SIRT1 [Reference Mei, Zhang, Yi, Huang, He and Tao118]. Therefore, SIRT2 has become a new focus of tumour research.

As a tumour-promoting factor, SIRT2 mainly promotes the immune escape of tumour cells by inducing immune avoidance, improving energy metabolism, and changing the tumour microenvironment, thereby inducing the development of tumours. In this article, we mainly describe the effects of SIRT2 on cancer through metabolic pathways. Studies have shown that SIRT2 can promote various cancers through various metabolic pathways. In gastric cancer, SIRT2, as a downstream target of miR-138, can increase PEPCK1-related metabolism, thereby promoting gastric cancer cell migration and invasion through the RAS/ERK/JNK/MMP-9 pathway [Reference Li, Zhang, Dorfman, Pan, Tang, Xu, Zhao, Zhou, Zhou, Wang, Yin, Shen, Kong, Friess, Zhao, Wang and Zou119, Reference Wang, Wu, Wang, Min and Chen120]. In colorectal cancer (CRC), Wnt/β-catenin inhibition can increase the expression level of the Wnt/β-catenin target gene SIRT2 and promote the proliferation of CRC cells [Reference Li, Zhou, Kim, Sengoku, Alstott, Weiss, Wang and Evers121]. In breast cancer, SIRT2 can be activated by NOTCH signalling, leading to the deacetylation and activation of high aldehyde dehydrogenase (ALDH1A1), thereby promoting breast cancer progression [Reference Zhao, Mo, Li, Zou, Cheng, Sun, Xiong, Guan and Lei122]. In liver cancer, SIRT2 can promote mitochondrial metabolism and inhibit the E-cadherin pathway, thereby promoting cancer cell invasion [Reference Huang, Zhao, Tang, Zhou, Li, Zhou, Yin, Wang, Pan, Dorfman, Ling and Zhang123]. In prostate cancer (PCa), SIRT2-mediated deacetylation of LIFR-K620 inhibits the progression of PCa [Reference Ding, Chi, Shao, Shi, Yu, Wang and Wang124]. In multiple myeloma (MM), a high expression of SIRT2 can act on the RAS/ERK signalling pathway to promote MM cell proliferation, thereby promoting MM progression [Reference Ding and Hao125]. In clear-cell renal cell carcinoma (ccRCC), SIRT2 deacetylates G6PD and increases its stability, thereby promoting ccRCC progression [Reference Ni, Yang, Agbana, Bai, Wang, Yang, Yi, Cheng, Zhang, Kuang and Zhu126]. In addition, the deacetylation of lactate dehydrogenase (LDH) by SIRT2 increases its enzymatic activity, leading to the accumulation of lactate and promoting tumour cell proliferation [Reference Zhao, Zou, Liu, Zhou, Mo, Wang, Xu, Dong, Xiong, Lei and Guan127]. Under conditions of nutrient excess, the activity of SIRT2 decreases, and the level of the acetylation of PKM2 increases, which increases its enzymatic activity and decreases lactate production and pyruvate accumulation, thereby resulting in a similar Warburg effect to promote cancer progression [Reference Park, Ozden, Liu, Song, Zhu, Yan, Zou, Kang, Jiang, Principe, Cha, Roh, Vassilopoulos and Gius128–Reference Lv, Li, Zhao, Lin, Chu, Zhang, Zha, Liu, Li, Xu, Wang, Huang, Xiong, Guan and Lei130].

As a tumour suppressor, SIRT2 can inhibit cancer by not only inhibiting fibroblast activity and angiogenesis but also inhibiting cancer through various metabolic pathways [Reference Ponnusamy, Zhou, Yan, Tang, Tolbert, Zhao, Gong and Zhuang131]. Studies have shown that T cells from SIRT2-deficient mice exhibit increased glycolysis and oxidative phosphorylation, resulting in enhanced proliferation and effector functions and exerting antitumour effects [Reference Hamaidi, Zhang, Kim, Wang, Iclozan, Fang, Liu, Koomen, Berglund, Yoder, Yao, Engelman, Creelan, Conejo-Garcia, Antonia, Mule and Kim60]. In breast cancer, SIRT2 not only promotes tumours but also suppresses tumours. For example, SIRT2 can inhibit the antioxidant activity of peroxiredoxin-1 (Prdx-1), rendering breast cancer cells sensitive to ROS-induced DNA damage and cytotoxicity, leading to apoptosis in breast cancer cells [Reference Fiskus, Coothankandaswamy, Chen, Ma, Ha, Saenz, Krieger, Mill, Sun, Huang, Mumm, Melnick and Bhalla132]. Alternatively, SIRT2 regulates the reversible acetylation of PHGDH through TIP60 and promotes the binding of PHGDH and RNF5 to induce PHGDH degradation, which reduces the serine and glycine levels and disturbs redox homeostasis, thereby inhibiting breast cancer cell proliferation [Reference Wang, Wan, Yu, Huang, Shen, Qi, Xiang, Chen, Arbely, Ling, Liu and Yu133]. In colorectal cancer, SIRT2 also inhibits CRC progression [Reference Li, Zheng, Cheng, Li, Mai, Jiang, Yang, Zhang, Li, Zheng, Wang and Qi134]. SIRT2 deacetylation is an important mechanism that regulates IDH1, which can exhibit tumour suppressor function by targeting the IDH1 K224 residue [Reference Wang, Ye, Yang, Liu, Wang, Chen, Jiang, Zhang, Jiang, Mustonen, Puolakkainen, Wang, Luo and Shen135]. Furthermore, in many other tumour cell types, SIRT2 can deacetylate ACLY and reduce its stability, thereby inhibiting tumour cell proliferation [Reference Lin, Tao, Gao, Li, Zhou, Guan, Xiong and Lei41].

In brief, the current evidence suggests that SIRT2 plays dual roles in cancer, and its specific role in cancer still needs to be revealed by further studies.

5.3. SIRT2 and Diabetes

In recent years, with the increasing number of patients with type 2 diabetes (T2D), increasing attention has been given to its pathogenesis and treatment. Studies have shown that T2D pathogenesis is mediated by abnormal glucose metabolism, insulin resistance (IR), and β-cell function. SIRT2 is a key hub in metabolic processes and, therefore, has been investigated as a potential therapeutic target for T2D [Reference Watanabe, Inaba, Kimura, Matsumoto, Kaneko, Kasuga and Inoue62, Reference Gomes, Fleming Outeiro and Cavadas90].

PEPCK1 can promote the utilization of glucose and glutamine via anabolism; thus, it is an important marker in evaluating T2D [Reference Li, Zhang, Dorfman, Pan, Tang, Xu, Zhao, Zhou, Zhou, Wang, Yin, Shen, Kong, Friess, Zhao, Wang and Zou119]. Studies have shown that inhibiting the deacetylase SIRT2 in the liver can promote the acetylation of PEPCK1, leading to its degradation and thereby inhibiting gluconeogenesis [Reference Zhang, Pan, Dorfman, Yin, Zhou, Huang, Liu and Zhao56, Reference Ren, Ye, Feng, Xu, Shen, Liu, Huang, Shen and Leng57].

IT in skeletal muscle is associated with a prediabetic state [Reference Parikh, Elgzyri, Alibegovic, Hiscock, Ekstrom, Eriksson, Vaag, Groop, Strom and Hansson136]. SIRT2 expression decreases with the progression of diabetic osteoarthritis (OA), resulting in increased H3 acetylation, oxidative stress, and inflammatory responses. Inhibiting SIRT2 accelerates the progression of diabetic OA, whereas the upregulation of SIRT2 may alleviate the development of diabetic OA by inhibiting the oxidative stress and inflammatory responses associated with H3 deacetylation. Furthermore, SIRT2 attenuates oxidative stress and mitochondrial dysfunction and increases insulin sensitivity in hepatocytes [Reference Lemos, de Oliveira, Naia, Szego, Ramos, Pinho, Magro, Cavadas, Rego, Costa, Outeiro and Gomes137].

Impaired hepatic glucose uptake (HGU) contributes to postprandial hyperglycaemia in T2D. In HFD-fed obese diabetic mice and db/db mice, SIRT2 activity decreased with decreasing hepatic NAD + levels, which enhanced GKRP acetylation and impaired HGU, whereas K126 deacetylation of GKRP alleviated glucose tolerance and impaired IR. Therefore, SIRT2 ameliorated HGU damage by deacetylating K126 of GKRP, dissociating glucose-dependent GCK from GKRP [Reference Watanabe, Inaba, Kimura, Matsumoto, Kaneko, Kasuga and Inoue62, Reference Zhou, Zhang, Zhu, Bai, Zhang, Zhu, Wang, Sheng, Yuan, Liu, Lu, Shao, Wang and Zhou63].

These studies show that SIRT2 protects against diabetes. However, Zheng et al. showed the opposite effects, suggesting that the haplotype of SIRT2 contributes to transcription factor binding and T2D susceptibility [Reference Zheng, Li, Sheng, Dai, Wang, Liu and Xu138]. Although the role of SIRT2 in diabetes is currently controversial, undoubtedly, SIRT2 may be a novel molecular target for future diabetes treatment.

5.4. SIRT2 and Cardiovascular Disease

Currently, cardiovascular disease is an important factor in human mortality, and its pathogenesis involves oxidative stress, the inflammatory response, apoptosis, autophagy, myocardial ischaemia-reperfusion, ageing, and energy restriction [Reference Zhang, Ma and Xiang139]. Therefore, studies have increasingly been conducted to explore the relationship between SIRT2 and cardiovascular disease.

Atherosclerosis is a main cause of cardiovascular disease. Studies have shown that during atherosclerosis, SIRT2 can inhibit the occurrence and development of atherosclerotic macrophages by inhibiting the polarization of macrophages [Reference Zhang, Ma and Xiang139]. Alternatively, SIRT2 can directly act on its target Nrf2/FOXO3/PARP1 and indirectly act on PARP1 by deacetylating BAG3, which alleviates the further aggravation of hypertension and oxidative stress, prevents intraluminal occlusion and stenosis from causing organic lesions, and avoids the occurrence of coronary heart disease (CHD) of myocardial ischaemia [Reference Shi, Zhang, Zhang, Gao, Liu, Chen and Yang97, Reference Liu, Ren, Liu, Li, Huang and Yang98, Reference Zhang, Zhang, Wu, Wu, You, Lu, Liu, Huang, Xu, Cao and Sun107, Reference Zhang, Zhang, Miao, Shi, Chen, Wu, Zou, Ma, You, Lu, Huang, Liu, Xu, Cao and Sun108]. Furthermore, in acute myocardial infarction (AMI), functional DNA sequence variants (DSVs) can alter the SIRT2 levels by affecting the transcriptional activity of the SIRT2 promoter, leading to the progression of AMI into severe disease [Reference Yang, Gao, Zhang, Pang, Cui, Liu, Wei and Yan140].

In heart failure, the downregulation of the creatine kinase (CK) system is a hallmark of impaired myocardial energy in failing hearts, and the acetylation of muscle creatine kinase negatively affects high-energy phosphate transfer in heart failure [Reference Walker, Chavez, Villet, Tang, Keller, Bruce and Tian141]. Deacetylation by SIRT2 reduces the acetylation of key lysine residues, improves dimer formation, and restores CK muscle form (CKM) activity in failing heart tissue, resulting in the amelioration of heart failure. In addition, miR-140-5p inhibitor experiments have shown that inhibiting miR-221-3p leads to SIRT2 activation, thereby targeting Nrf2/FOXO3, inhibiting cardiomyocyte apoptosis and oxidative stress, and relieving cardiac exhaustion [Reference Zhao, Xue, Li, Feng, Zeng, Chen, Duan, Zhang, Li, Han and Yang142, Reference Zhuang, Xia, Chen, Ye, Hu, Li and Hou143].

In cardiac hypertrophy, SIRT2 acts as a cardioprotective deacetylase [Reference Tang, Chen, Wang, Wang, Liang, Zheng, Lu, Zhao, Hao, Zhang, Zou, Liu and Chen144]. SIRT2 binds and deacetylates LKB1 at lysine 48, promoting the phosphorylation of LKB1 and its translocation from the nucleus to the cytoplasm, which activates LKB1-AMPK signalling. Some other targets of SIRT2, such as FOXO1 and PGC1-α, are also known regulators of cardiac hypertrophy. FOXO1, FOXO3a, and PGC1α are also downstream of LKB1-AMPK signalling. Therefore, the activation of LKB1-AMPK signalling may be a core mechanism underlying SIRT2-mediated cardioprotective effects. This hypothesis was confirmed in a study by Mei et al., who showed that CSN6 was partially dependent on the stabilization of the Nkx2.2 protein, which is a transcriptional repressor of SIRT2 that inhibits SIRT2 and promotes cardiac hypertrophy [Reference Mei, Wang, Hu and Xiong145]. Gu et al. showed that PHD finger protein 19 (PHF19) can inhibit the expression of SIRT2, thereby promoting Ang II-induced cardiomyocyte hypertrophy [Reference Gu, Cheng, Wang, Sun and Li146]. Furthermore, in myocardial infarction, maintaining SIRT2 activity can interfere with the interaction between CDK5 and SIRT2 through the interaction between LncHrt and SIRT2, thereby activating the downstream LKB1-AMPK cascade to maintain the balance of cardiac metabolism [Reference Liu, Kataoka, Wang, Pu, Dong, Fu, Zhang, Gao, Liang, Pei, Xiao, Qiu, Hong, Chen, Zhao, Zhu, He, Hu, Nie, Zhu, Yu, Cowan, Hu, Wang, Wang and Chen147]. Collectively, these studies have shown that SIRT2 is a cardioprotective deacetylase in cardiovascular disease and could be a therapeutic target for cardiovascular disease.

5.5. SIRT2 and Other Metabolic Diseases

Recent studies have shown that the NAD+/SIRT2 pathway plays an important role in regulating nonalcoholic fatty liver disease (NAFLD) [Reference Zhang, Xu, Zhang, Wang, Yang, Lou, Zhao, Aa, Wang and Xie148]. NR (nicotinamide riboside) stimulates SIRT2, promotes SIRT2 deacetylation, and stabilizes Fndc5 to prevent HFD-induced NAFLD; SIRT2 also deacetylates and stabilizes CCAAT/enhancer-binding protein beta (C/EBPβ) to prevent NAFLD; alternatively, NAFLD can be treated by targeting the SIRT2-HNF4α pathway [Reference Ren, Hu, Wang, Kang, Feng, Zhang, Zhou, Liu and Yuan43, Reference Li, Sun, Fu, Ouyang, Zhao, Su, Ji, Sun, Zhu, Zhang, Ma, Lan, Zhao, Tong, Li, Shen and Wang149, Reference Zhang, Long, Ruan, Wei, Zhang, Wo, Huang, Lin, Wang, Xia, Zhao, Liu, Zhao and He150]. Furthermore, during hepatic ischaemia-reperfusion (I/R) injury, SIRT2 upregulates the MAPK pathway through MKP-1 deacetylation, thereby enhancing the inflammatory response and cell death, leading to the exacerbation of postoperative liver injury [Reference Wang, Koh, Zhou, Bae, Lee, Bang, Ka, Oh, Bae and Park151].

5.6. Application of SIRT2 in Disease

As previously mentioned, SIRT2 enables crosstalk between gene expression regulation and metabolism and plays an important role in related diseases; thus, it can be used as a key target for disease treatment or drug development. In mouse models of HD and acute cerebral ischaemia, AK-7, an inhibitor of SIRT2, showed neuroprotective effects [Reference Chopra, Quinti, Kim, Vollor, Narayanan, Edgerly, Cipicchio, Lauver, Choi, Silverman, Ferrante, Hersch and Kazantsev152, Reference Wu, Lu, Wei, Xu and Liu153]. The cardiotoxicity caused by the antineoplastic drug doxorubicin can be alleviated by increasing SIRT2 activity with limonoid or the adiponectin agonist ADP355 [Reference Zhao, Xue, Li, Feng, Zeng, Chen, Duan, Zhang, Li, Han and Yang142, Reference Deng, Huang and Wu154]. In the treatment of NAFLD, silibinin can increase the activity of SIRT2, thereby protecting the liver [Reference Zhang, Xu, She, Wang, Yang, Sun, Zhang, Yan, Wei, Aa, Liu, Wang and Xie155].

In addition, numerous studies have shown that SIRT2 has different expression characteristics in different diseases; thus, it can be used as a biomarker of disease to judge the occurrence, development, and prognosis of disease. In tumours, SIRT2 can be used as a biomarker for the clinical diagnosis and treatment of tumours, such as to predict the development of the epithelial-mesenchymal transition (EMT), hepatocellular carcinoma (HCC), and endometrial cancer (EC) [Reference Zhao, Zhang, Li, Xu, Zhang, Liu, Liu, Chen, Yang and Zhang156–Reference Wang, Yan, Wang, Yin, Chang, Liu and Wu158]. SIRT2 predicts future atrial fibrillation prevalence in coronary artery disease (CAD) and myocardial infarction [Reference Anand, Rector, Kuskowski, Snider and Cohn159, Reference Kalstad, Myhre, Laake, Opstad, Tveit, Solheim, Arnesen and Seljeflot160].

Overall, currently, SIRT2 is mainly applied to screen drugs as therapeutic targets for disease or as a biomarker to facilitate the diagnosis and prognostic evaluation of disease. However, the clinical application of SIRT2 requires further research.