Quercetin

Quercetin as a protective agent for liver diseases: A comprehensive descriptive review of the molecular mechanism

Xingtao Zhao1,2,3 | Jing Wang1,2,3 | Ying Deng1,2,3 | Li Liao1,2,3 | Mengting Zhou1,2,3 | Cheng Peng1,2,3 | Yunxia Li1,2,3

Abstract

Quercetin is the major representative of the flavonoid subgroup of flavones, with good pharmacological activities for the treatment of liver diseases, including liver steatosis, fatty hepatitis, liver fibrosis, and liver cancer. It can significantly influence the development of liver diseases via multiple targets and multiple pathways via anti- fat accumulation, anti-inflammatory, and antioxidant activity, as well as the inhibition of cellular apoptosis and proliferation. Despite extensive research on understanding the mechanism of quercetin in the treatment of liver diseases, there are still no targeted therapies available. Thus, we have comprehensively searched and summa- rized the different targets of quercetin in different stages of liver diseases and concluded that quercetin inhibited inflammation of the liver mainly through NF-κB/TLR/NLRP3, reduced PI3K/Nrf2-mediated oxidative stress, mTOR activation in autophagy, and inhibited the expression of apoptotic factors associated with the development of liver diseases. In addition, quercetin showed different mechanisms of action at different stages of liver diseases, including the regulation of PPAR, UCP, and PLIN2-related factors via brown fat activation in liver steatosis. The compound inhibited stromal ECM deposition at the liver fibrosis stage, affecting TGF1β, endo- plasmic reticulum stress (ERs), and apoptosis. While at the final liver cancer stage, inhibiting cancer cell proliferation and spread via the hTERT, MEK1/ERK1/2, Notch, and Wnt/β-catenin-related signaling pathways. In conclusion, quercetin is an effective

1 | INTRODUCTION

Millions of people around the world still suffer from acute or chronic liver diseases over the past 30 years, coming a substantial economic burden. Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease globally, with an incidence of up to 40%, followed by hepatitis B virus (HBV), hepatitis C virus (HCV), and harmful alcohol liver disease (ALD), accounting for 30%, 15%, and 11%, respectively (Xiao et al., 2019). Hepatic steatosis is increasingly recognized as a crucial pathological feature early in the disease, progressing with sustained oxidative stress and inflammation, then stimulate the pro- gression of liver fibrosis to cirrhosis and even liver cancer (Ajmera & Loomba, 2021). Currently, there is still a lack of effective drugs and treatments for liver diseases due to poor efficacy and toxic side effects (Liebe et al., 2021). Therefore, it is crucial to find more effec- tive drugs for liver diseases therapy.
Many natural products provide a new clue for the treatment of liver diseases. In the United States and other western countries, com- pared with synthetic drugs, anti-liver herbs are used by more than 65% of patients due to their wider availability, pharmacological activ- ity, and chemical diversity and lower side effects. Quercetin (e.g., Figure 1) is the major representative of the flavonoid subclass of flavones, found in fruits (such as blueberries and apples) and vegeta- bles (including onions and broccoli). Many herbal medicines also con- tain quercetin, including Root of Red Thorowax, Penthorum chinense Pursh, and Forsythia suspensions. In recent years, quercetin has shown remarkable efficacy in liver diseases therapy (Miltonprabu et al., 2017) including improving metabolic functioning, lowering serum cholesterol, reducing inflammation and oxidative stress, inhibiting cell proliferation and various potential biological activities (e.g., Figure 2) (Batiha et al., 2020). However, there is no systematic review and comparison on the mechanism of quercetin in different stages of liver diseases. This review may provide more precise targets and a theoretical basis for the further study of the role of quercetin in the treatment of liver diseases.

2 | ANTILIVER STEATOSIS PROPERTY OF QUERCETIN

Steatosis is the result of lipid metabolism disorders in adipocytes induced by overeating or alcohol consumption. While browning induces the conversion of beige adipocytes distributed in white adipose tissue (WAT) to brown-like adipocytes (BAT), promotes lipolysis, thermogene- sis, triglyceride (TG) clearance, glucose clearance, and insulin sensitivity (Kuo, Lee, & Sessa, 2017; Shapira & Seale, 2019), and has become a potentially crucial and effective strategy for its associated metabolic dis- orders (Ikeda, Maretich, & Kajimura, 2018). Recent studies have shown that quercetin played a crucial role in regulating lipid metabolism homeostasis through browning and lipophagy-related response. The molecular pathways related to this pathology are as follows.

2.1 | AMPK

AMP-activated protein kinase (AMPK), a key regulator of energy bal- ance, plays a crucial role in energy metabolism and its activation pro- tects the liver from TG accumulation (Woods et al., 2017). AMPK stimulates the catabolic adenosine triphosphate (ATP) production pathway (i.e., fatty acid oxidation), induces BAT browning, and maintains mitochondrial integrity and function (Lo´pez & Tena-Sempere, 2017). The downstream protein SIRT1 acts as potential tar- gets for metabolic syndrome (C. Chen, Zhou, Ge, & Wang, 2020).
Previous study demonstrated that quercetin attenuated HFD- induced obesity mice through activating AMPKα1/ SIRT1, suggesting that quercetin reduced fat accumulation through AMPK pathway(Pei et al., 2021). 3 T3-L1 adipocyte promotes fat accumulation in high serum culture. After quercetin treatment, the phosphorylation and upregulation of AMPK and acetyl-CoA carboxylase (ACC) in 3 T3-L1 preadipocyte exhibited antilipogenic activity (Q. Wu, Wang, Fu, & Ren, 2019). In HFD-induced mice, other study showed that AMPK phosphorylation induced by quercetin partially regulated the 3 T3-L1 adipocyte browning through upregulation of SIRT1 and PGC1α expression (S. G. Lee, Parks, & Kang, 2017). Quercetin also activated the sympathetic stimulation via AMPK/PPARγ pathway to increase WAT browning and BAT activity (Choi, Kim, & Yu, 2018). It is suggested that quercetin increased fat browning to reduce fat accu- mulation mainly by phosphorylating AMPK.

2.2 | UCP

Uncoupling proteins (UCP), members of the mitochondrial anion car- rier superfamily, are involved in the regulation of energy homeostasis and lipid metabolism (Ježek, Holendov´a, Garlid, & Jabu˚ rek, 2018). UCP1, specific for WAT, is thought to be crucial for increased thermo- genesis and promotes lipid browning in adipose tissue (Chouchani, Kazak, & Spiegelman, 2019). UCP2, a mitochondrial inner membrane protein that mediates proton leakage, is uncoupled ATP synthesis and ROS production negatively (Sreedhar & Zhao, 2017). A recent study has shown that mice fed a HFD supplemented with 1% quercetin (HFDQ-fed mice) had increased expression of non-shivering thermogenesis genes in BAT, including UCP1, PGC1α, and mtTFA(Pei et al., 2021). Quercetin alone (Kuipers et al., 2018), or in combination with resveratrol (Arias et al., 2017) both induced UCP1 protein expression leading to WAT browning in rats. And after treated with PPARγ antagonists, their combination also lead to over- expression of UCP2 and increased PPAR-α expression in HFD-fed rats (Castrejo´n-Tellez et al., 2016), which suggest that quercetin affected fat browning through the interaction between UCP and PPAR.

2.3 | PPAR

Peroxisome proliferator-activated receptor (PPAR) plays a crucial role in the regulation of lipid and glucose homeostasis and is generally classified into three subtypes. While PPARα and PPARγ show oppo- site pharmacological effects on lipid degeneration (Christofides, Konstantinidou, Jani, & Boussiotis, 2021; Dubois, Eeckhoute, Lefeb- vre, & Staels, 2017).

2.3.1 | PPARγ

PPARγ is a major regulator of WAT differentiation, which controls FA uptake and adipogenesis and regulates the activity of PGC1α and UCP1 activity in BAT to improve glucose homeostasis and remodel adipose tissue and insulin resistance (J. E. Lee, Schmidt, Lai, & Ge, 2019). In HFD-fed rats, quercetin reduced adipocyte size and enhanced angiogenesis and adipogenesis without changes in eWAT weight and the eWAT/brown BAT ratio, including two central adipogenic regula- tors, that is, PPARγ and C/EBPα, and proteins involved in mature adi- pocyte formation, that is, FAS and adiponectin (Perdicaro et al., 2020).
In 3 T3-L1 adipocyte, quercetin treatment increased the expression level of UCP1 in HFD mice, while PPARγ antagonist reversed this result and enhanced WAT browning and BAT activity (Choi et al., 2018). Combined with resveratrol, quercetin induced WAT browning and increased UCP1 protein expression in rats (Arias et al., 2017). And quercetin increased UCP2 expression, which was associated with changes in PPAR-γ and PPAR-α expression (Castrejo´n-Tellez et al., 2016). Further, quercetin activated the PPARγ-LXRα pathway to repress UCP1 gene transcription in C57BL/6 mice (K. Ren, Jiang, & Zhao, 2018) through increasing the protein levels of PPAR γ and its transcriptional activity to upregulate ABCA1 (L. Sun et al., 2015). Thus, quercetin enhanced fat browning via PPARγ-mediated LXRα-UPC1 signaling pathway, which is a novel target for reducing liver steatosis (Houghton, Kerimi, Tumova, Boyle, & Williamson, 2018).

2.3.2 | PPARα

PPARα (NR1C1) is abundant in the liver and is the main nuclear recep- tor for fatty acid β-oxidation (Y. Wang, Nakajima, Gonzalez, & Tanaka, 2020). In WAT, PPARα induces the expression of mitochon- drial acyl coenzyme A (CoA) dehydrogenase upon activation by browning, thereby stimulating the transcription of the hepatic fatty acid transporter protein to reduce plasma TG and low-density lipoprotein cholesterol (LDL-C) levels and increase HDL-C and directly or indi- rectly involved in UCP1 expression (Ruscica, Busnelli, Runfola, Corsini, & Sirtori, 2019). In BAT, PPARα acts synergistically with PGC1α to stimulate lipid oxidation as well as thermogenesis (Padovano, Podrini, Boletta, & Caplan, 2018).
Quercetin normalized the expression of hepatic genes associated with steatosis by decreasing the expression of PPARα, which in turn regulated SREBP1c, fatty acid synthase (FASN) and increased the expression of CPT1 in vivo and vitro (Kobori, Masumoto, Akimoto, & Oike, 2011; L. L. Wang et al., 2016). Quercetin enhanced the binding of PGC-1α to PPARα, thereby protecting mitochondrial function in HepG2 cells (Houghton et al., 2018). A recent study has shown that HFDQ-fed mice had increased expression of nonshivering thermogenesis genes in BAT, including PGC1α, cell death-inducing DFFA-like effector A (CIDEA) may attenuate obesity(Pei et al., 2021). Thus, Quercetin-mediated PPARα/ PGC-1α signaling pathway was the key to regulate fatty acid β-oxidation and reduce fat accumulation.

2.4 | Lipophagy

In adipose tissue, lipid droplets (LDs) (Olzmann & Carvalho, 2019) are a core cytoplasmic component of white adipocytes. Lipophagy, first identified in the liver, activates the white adipocyte differentiation process and inhibits lipid droplet formation and autophagy markers such as LC3 and p62 (Ward et al., 2016), which is a novel target for lipolysis (Ro et al., 2019).
Quercetin exerted hepatoprotective effects by downregulating p62, mechanistic target of rapamycin (mTOR), and significantly inhibiting CD36 and LC3II protein expression to reduce autophagic lysosomal degradation of ox-LDL induced by high-fat diet in mice (L. Liu, Gao, Yao, & Gong, 2015). Quercetin also improved TG deposi- tion in the liver via promoting very low-density lipoprotein (VLDL) formation and lipophagy through 1REα/XBP1s pathway in HFD-fed rats and FFA-induced HepG2 cells (X. Zhu et al., 2018). In addition to phagocytosis of accumulated LDs, autophagy can also remove dam- aged mitochondria and prevent further development of the disease. Among them, PTEN-induced putative kinase1 (PINK1) mediates the recruitment of Parkin outside the mitochondria to induce the ubiquitination of mitochondrial outer membrane protein and the sub- sequent degradation of mitochondria in the autophagosome to prevent the ER stress caused by the aggravation of liver diseases (Porras et al., 2017). PINK1, LC3II, and Beclin1 expression increased, reduced p62 levels, and quercetin prevented the inhibition of mito- chondria by HFD-fed mice, thereby preventing nonalcoholic fatty liver diseases in mice (NAFLD) (P. Liu et al., 2018). Therefore, the blocking of quercetin to the unfolded protein response (UPR) associated with reticular stress may be related to the progression of steatosis to steatohepatitis (Gonz´alez-Rodríguez et al., 2014). The regulation of Parkin induced mitochondria by quercetin is a potential therapeutic target for liver diseases therapy.

2.4.1 | mTOR

mTOR is a crucial regulator of adipose tissue formation and lipid stor- age regulated by AMPK (Olzmann & Carvalho, 2019). mTORC1 is a major regulator of autophagy in adipose tissue, in an autophagy- independent manner, inhibits adipogenesis in 3 T3-L1 preadipocytes (H. Wang et al., 2019), and is an essential component of the browning process in white adipose depots (D. Liu et al., 2016). Quercetin mediated autophagy through mTOR and thereby regu- lated the protein expression of autophagy marker proteins, microtubule-associated protein 1, LC3II, and autophagic autophagosome bridging p62 and was able to reduce the ox-LDL accumulation observed in HFD-fed mice to reduce fat accumulation (L. Liu et al., 2015). However, the exact mechanism needs to be fur- ther investigated.

2.4.2 | PLIN2

The lipid-binding protein perlipin 2 (PLIN2) (X. Liu, Lu, Song, & Blackman, 2016) is the only constitutive and ubiquitously lipid droplet protein that is expressed, and PPARγ activation upregulates the expression of the PLIN2 gene, which induces hepatic steatosis (S. Xu, Zhang, & Liu, 2018). Quercetin promoted ethanol-induced lipophagy by decreasing PLIN2 levels, activating AMPK activity, and increasing colocalization with hepatic LC3II protein in mice (Zeng et al., 2019), suggesting PLIN2 mediated by AMPK is a novel target of action of quercetin lipofuscin.

2.5 | Apoptosis-related factors

Apoptosis plays a crucial role in the developmental process of liver and in maintaining the homeostasis of the internal environment. While we need to clarify their respective signaling pathways to find out whether they are the focus of research and whether they have any effect on lipid accumulation. Quercetin significantly inhibited the level of tumor suppressor P53, Bax, cleaved-cas3 expressionl and increased Bcl-2 expression to reduce apoptosis in vivo and in vitro (Y. Zhang et al., 2020). Quercetin inhibited apoptotic cell death during CCl4-induced steatosis (Esrefoglu et al., 2017), and quercetin had protective effect on mice against ConA-induced hepatitis in mice, and the regulation of related apoptotic factors Bax, Bcl-2, Beclin-1, and LC3 via tumor necrosis fac- tor receptor-associated factor 6 (TRAF6)/c-Jun NH2-terminal kinase (JNK). Quercetin pretreatment significantly affected the expression of p62 and caspase 9 (L. Wu et al., 2017). Quercetin activated JNK, which inhibited caspase-3 activation and reduced p53 and Bax expression to suppress apoptosis (K. H. Lee & Yoo, 2013). In HepG2 cells, quercetin prevented isoniazid-induced apoptosis by activating the SIRT1/ERK pathway and significantly affected Bcl-2 expression and reduced Bax, caspase-3 and caspase-9 cleavage to significantly abrogate INH-induced apoptosis (Y. Zhang et al., 2019). On oxaliplatin-induced hepatotoxicity in mice, quercetin nanoemulsion mainly reduced the immunopositivity of apoptosis marker caspase-3 and decreasing neutrophil migration as measured by peroxidase (MPO) activity (Schwingel et al., 2014). Quercetin-induced apoptosis can also be induced by inhibition of FASN in HepG2 cells (Bedi et al., 2020), but the exact mechanism is unclear and remains to be further investigated in depth afterward.
Taking together, the data from experiments with animal models and cell cultures as described above have implicated that quercetin may a modulator of hepatic steatosis (Gori et al., 2021), and the possi- ble mechanisms of quercetin treatment in hepatic steatosis may include browning fat and regulating lipid autophagy, improving antiox- idant stress, and reducing inflammation (Figure 3, Table 1).

3 | ANTIFATTY HEPATITIS PROPERTY OF QUERCETIN

Excessive ROS can exacerbate the progression of liver diseases from liver steatosis to fatty hepatitis, causing serious damage to the antioxi- dant system in the body, in which the PI3K/Akt pathway plays a crucial role in the body’s resistance to oxidative stress. In addition, the increase of ROS promotes the production of TNF-α and aggravates mitochondrial damage and also initiates NF-κB, IL-1β, and other inflammatory factors, leading to the infiltration of central granulocytes, contributing to the increase of inflammatory response, and eventually leads to apoptosis (Mansouri, Gattolliat, & Asselah, 2018). Therefore, inhibiting the occurrence of oxidative reac- tion and inflammation as well as the cross-talk between them is the key to prevent and treat liver diseases. Studies had shown that quer- cetin alleviated or reversed the occurrence and occurrence of diseases by reducing oxidative stress and inflammation. The molecular path- ways related to this pathology are as follows.

3.1 | P2X7R

As an adenosine triphosphate-gated ion channel, P2X7R can be activated by high levels of extracellular ATP, activates PI3K/Akt- mediated oxidative stress signaling pathway via different organs or cell types (Markwardt, 2020). P2X7R, which is upstream of NLRP3, can lead to inflammatory activation and cytokine expression in monocytes and also be dependent on TLR4 ligands to mediate caspase1 activation (Di Virgilio, Dal Ben, Sarti, Giuliani, & Falzoni, 2017).
Recently, it was reported that inhibition of P2X7R activation by quercetin also attenuated Keap 1/Nrf2 oxidative stress in alcoholic fatty liver in zebrafish (X. Zhao et al., 2020). Dihydroquercetin modu- lated adipogenesis and improved alcoholic hepatic steatosis by modu- lating P2X7R-NLRP3-inflammatory vesicle activation mediators in HepG2 cells (Y. Zhang et al., 2018), suggesting P2X7R is a new target and needs further study.

3.2 | PI3K/Akt

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is activated by growth factors and controls cell survival, proliferation, and metabolism (Scheid & Woodgett, 2001). The nuclear factor carotenoid-derived 2-like 2 (NFE2L2, also known as Nrf2) may be a downstream signaling target of PI3K/Akt (Han et al., 2017). A major transcription factor regulating antioxidant and anti-inflammatory genes, Nrf2, is closely associated with intraliposomal homeostasis (Hayes & Dinkova- Kostova, 2014) and is the most important transcription factor induced by the antioxidant response (X. Chen et al., 2019).
Quercetin inactivated phosphatidylinositol 3-kinase/ Akt- dependent glycogen synthase kinase (GSK-3β) (K. H. Lee & Yoo, 2013). Quercetin induced HO-1 stimulation of hepatic mitochondrial oxidative metabolism via the Nrf-2 pathway. Quercetin contrib- uted to the prevention of obesity-induced fatty hepatitis in mice (C. S. Kim et al., 2015). Moreover, quercetin regulated the P2X7R- mediated PI3K/Keap1/Nrf2 oxidative stress signaling pathway. It also had a similar hepatoprotective mechanism in zebrafish with respect to the alcoholic fatty liver model (X. Zhao et al., 2020).

3.3 | NF-κB

As the downstream signaling pathway of PI3K (Overman, Chuang, & McIntosh, 2011), NF-κB is the most prevalent transcription factor that plays a crucial role in the inflammatory process (An et al., 2002). Acti- vation of NF-κB is caused by signal-induced degradation of IκB protein. NF-κB sequentially turns on the expression of its own blocker, IκB. The newly synthesized IκB then reinhibits NF-κB, resulting in a self-feedback loop that leads to oscillations in NF-κB activity (Nelson et al., 2004). And a complex signaling pathway can be activated by TLR4 and TLR2 that includes activation of mitogen-activated protein kinases (MAPK) and inhibitory κB (IκB), thereby inactivating NF-κB and inflammatory cytokines (L. Ji et al., 2014).
Recent study has shown that quercetin significantly attenuated systemic IR and inflammation in HFD-fed rats (Perdicaro et al., 2020). Quercetin attenuated the expansion of adipose tissue in WAT and reduced serum IL-6 and MCP-1 mRNA levels in HFD-induced obese mice (Forney, Lenard, Stewart, & Henagan, 2018). In addition, querce- tin even the combination with catechins reduced metabolic index such as insulin concentration and insulin resistance (HOMA-IR), as well as fatty HFD expression TNF-α levels in adipose tissue of fat-fed rats (Vazquez Prieto et al., 2015). Quercetin contributed to inflammatory responses was suppressed by inhibiting the TLR4/NF-κB signaling pathway in RAW264.7 cells (T. Li, Li, Liu, Liu, & Li, 2019) which is critical links between inflammation and fibrosis (Anthoney, Foldi, & Hidalgo, 2018).
Quercetin also reversed intestinal flora imbalance and associated endotoxemia-mediated TLR-4 pathway and subsequently inhibits inflammatory vesicle response (NF-κB) and reticulostriatal pathway activation, resulting in blockade of dysregulated lipid metabolism gene expression in mice (Porras et al., 2017). The effect of quercetin on osteoarthritis quercetin was mediated through inhibition of SIRT1/Akt/NF-κB signaling pathway on IL-1β-induced chondrocytes in rats via anti-inflammatory effects in HFD diet in gerbils (Ying et al., 2013). In vitro, it evidently relieved INH-induced cell viability loss and apo- ptosis in L02 cells. Furthermore, the studies on mechanisms eluci- dated that quercetin remarkably elevated the expression of SIRT1 and suppressed NLRP3 inflammasome activation (Y. Zhang et al., 2020). Taking together, the data from experiments with animal models and cell cultures as described above have implicated that oxidative reaction and inflammation as well as the cross-talk between them is the key mechanisms of quercetin treatment in fatty liver diseases (Figure 4).

4 | ANTILIVER FIBROTIC PROPERTY OF QUERCETIN

The massive accumulation of extracellular matrix (ECM) is the main cause of liver fibrosis, which mainly involves abnormal synthesis of matrix metalloproteinases and their inhibitors, resulting in increased hepatic ECM content through TGF-β and cytokine and chemokine production, and there is increasing evidence that endoplasmic reticulum stress (ERs) plays a crucial role in the development of liver dis- eases. Recently, several studies have found that quercetin had significant antihepatic fibrotic effects. Quercetin moderated or reversed tissue fibrosis injury by reducing ECM deposition, ERs, and decreasing oxidative stress and inflammatory response. The molecular pathways related to this pathology are as follows.

4.1 | TGFβ

TGF-β1 activates hepatic stellate cells (HSCs) to produce large amounts of ECM, a pleiotropic cytokine that regulates immune response, embryogenesis and cell cycle, and plays a crucial role in th process of liver fibrosis; Through the inhibition of MMP and the natu- ral inhibitor TIMP, TGF-β1 can inhibit ECM degradation. Second, TGF- β1 induces myofibroblast formation via tubular EMT. Third, TGF-β1 induces matrix production via SMAD3-dependent or non-SMAD (e.g., MAPK, NF-kB and PI3K, mTOR pathway)-related mechanisms (K. K. Kim, Sheppard, & Chapman, 2018). Quercetin prevented liver fibrosis by inhibiting stellate cell acti- vation and autophagy through the TGF-β1/Smads pathway in BDL or CCl4-induced mice cirrhosis models (L. Wu et al., 2017). The critical role of quercetin in regulating M1 macrophage polarization in CCl4-induced liver inflammation and fibrosis in mice was medi- ated by Notch1 signaling pathway via TGF-β/Smad signaling. It issuggested that TGF-β/Smad is a potential target for the treatment of liver fibrosis, and Notch may be cross-interfered (X. Li et al., 2018).

4.2 | MMPs/TIMPs

Matrix metallopeptidases (MMPs) are participated in the degradation of various components of the ECM and basement membrane and are one of the indicator components of liver fibrosis (Cui, Hu, & Khalil, 2017). Quercetin treatment reduced fibrosis index and prevented liver fibrosis by inducing HSC apoptosis, even combination with ellagic acid downregulated MMP9 and MMP2 expression showing a therapeutic effect on thioacetamide-induced liver fibrosis in rats (Afifi, Ibrahim, & Galal, 2018). Our results showed that quercetin reduced bile duct ligation (BDL) or CCl4 liver fibrosis in mice, inhibited ECM formation, and regulated MMP-9 and tissue inhibitor of metalloproteinase (tissue inhibitor of metalloproteinase, TIMP)-1 (L. Wu, Zhang, et al., 2017). Although the MMPs/TIMPs system is participated in the regulation of fibrotic injury, the molecular mechanism by which it exerts the antifibrotic effects of quercetin via the regulation of the MMPs/TIMPs system is not fully understood. Therefore, more studies are needed to fully understand it.

4.3 | ERs

ERs are linked to the process of hepatic fibrosis through the UPR- mediated activation of IRE1/XBP1, PERK-eIF2α-ATF4-CHOP, and ATF6 activation, which in turn induces apoptosis (Dolai, Pal, Yadav, & Adak, 2011; Iurlaro & Muñoz-Pinedo, 2016), The sustained inflamma- tory response induces the release of ERS-promoting genes Bcl-2, p53, and cytochrome C, leading to massive apoptosis of hepatocytes (Wei & Huang, 2019). However, in large numbers sustained ERS pro- motes apoptosis of activated HSC, yet facilitates the reduction or recovery of liver fibrosis (J. Liu, Wang, & Lin, 2019). Reports showed that in rat HSC and LO2 hepatocytes, quercetin activated endoplasmic reticulum stress in hepatic stellate cells and induced downregulation of Bcl-2 and upregulation of Bax, increases the cleaved forms of cytochrome C, caspase-9, caspase-3, and PARP-1 in the cytoplasm, upregulated phosphorylation of PERK and cleavage of IRE1 and ATF6, and increased transcriptional and transla- tional levels of calmodulin and CHOP to stimulate mitochondrial apo- ptosis (He, Hou, Fan, & Wu, 2016).

4.3.1 | Apoptosis

Bcl-2 and Bax expression exerts a crucial role in membrane permeabil- ity by regulating apoptosis in mitochondrial outer membrane cells. Bcl-2/Bax ratio may be the key sensory switch that determines the onset of apoptosis (H. D. Xu & Qin, 2019). Quercetin treatment induced HSC apoptosis (Hern´andez-Ortega et al., 2012) and inhibited the hepatic fibrosis process by modulating Bcl-2/Bax signaling in CCl4-induced liver fibrosis in rats (R. Wang, Zhang, Wang, Song, & Yuan, 2017).

4.4 | TLRs/NF-κB and PI3K/Akt

Collagen synthesis and fibrosis formation are due to activation of stel- late cells by Kuppfer cells and increased transcription of proinflammatory cytokines (e.g., TNF-α). Control of the inflammatory process could be a potential therapeutic target to inhibit disease pro- gression (Zhangdi et al., 2019). NF-κB, a multifunctional transcription factor, is involved in immune and inflammatory responses. TLRs play an important role in the inflammatory response/immune response, among others (Ciesielska, Matyjek, & Kwiatkowska, 2020). TLR4, as an upstream target of NF-κB, can be used through MyD88 and other related factors to regulate the course of inflammation (Liang, Yang, Liu, Sun, & Wang, 2018). There is growing evidence that TLR2 and TLR4 signaling not only activate the ASK1/p38 MAPK/NF-KB signal- ing pathway but also stimulate the ERK/JNK and PI3K/Akt pathways in a MyD88-independent manner (H. Li et al., 2021).
Quercetin inhibited the expression of the proinflammatory cyto kines TNF-α, IL-6, IL-1β, Cox-2 and the degradation of IкBα to suppress NF-κB activation (Hern´andez-Ortega et al., 2012) and HSC activation, with inhibitory effects on the liver fibrosis process (R. Wang et al., 2017). Quercetin protected mouse liver from CCl4 through TLR2/4 and MAPK/NF-κB pathways-induced inflammatory responses in fibrotic injury and inhibited CCl₄-induced TLR2, TLR4, JNK, ERK, p38, and NF-κB activities, confirming the pro-inflammatory nature of TLRs/ MAPK/NF-κB pathway in mouse liver (Ma, Li, Xie, Liu, & Liu, 2015). PI3K/Akt promotes adhesion and migration of HSCs and liver fibrosis formation, and blocking PI3K/Akt reduces type I collagen expression. Quercetin prevented hepatic fibrosis via inhibiting the activation of HSC cell and reduced autophagy through PI3K/Akt path- way (L. Wu, Zhang, et al., 2017). Taking together, the data from experiments with animal models and cell cultures as described above have implicated that the possible mecha- nisms of liver fibrosis injury by reducing ECM deposition, ERs, and decreasing oxidative stress and inflammatory response (Figure 5, Table 2).

5 | ANTILIVER CANCER PROPERTY OF QUERCETIN

Hepatocellular carcinoma is a process of gradual accumulation of xenomorphic cells, abnormal DNA structure, and changes in genetic material, which eventually leads to accelerated cell proliferation and induction of apoptosis. There is no effective therapy yet, while recent studies have shown that quercetin played crucial roles in the development of hepatocarcinogenesis through hTERT, MEK1/ERK1/2, Notch, Wnt/β-catenin, oxidative stress signaling pathway PI3K/Akt, and inflammatory NF-κB pathway, and their organismal mechanisms need to be further studied in depth. Nanoparticles can act as drug carriers, target tumors, and enhance the bioavailability. Many new formula- tions have been developed to target cancer. Nanoparticles quercetin (NQ) have been widely studied, among other thingsmPEG750-b-OCL- Bz micelles are a promising multi-functional vehicle for codelivery of QCT and SPIONs for disease monitoring and therapies of hepatocellu- lar carcino (Srisa-Nga, Mankhetkorn, Okonogi, & Khonkarn, 2019). The molecular pathways related to this pathology are as follows.

5.1 | hTERT

Human telomerase reverse transcriptase (hTERT), the main subunit of the telomerase core, is essential for chromosome stability and integrity. Inhibition of hTERT has been found to prevent prolifeliration and inducing apoptosis effectively, which is a tumor marker for early detection of liver tissue cancer (Le~ao et al., 2018; Stögbauer, Stummer, Senner, & Brokinkel, 2020). NQ was more effective in inhibiting HCC cell proliferation, cell migration, and colony formation, thereby inhibiting HCC progres- sion. The protein of enhancer-binding protein-2 (AP-2) can bind to hTERT at corresponding sites and exert biological effects through activating some cancer-related gene activation and signaling path- way such as mTOR-mediated PI3K/Akt (Dogan & Biray Avci, 2018). NQ reduced AP-2β expression via hTERT inhibition and decreased its binding to the hTERT promoter (K. W. Ren et al., 2017), suggesting a potential target for the treatment of liver cancer.

5.2 | MEK1/ERK1/2

The mitogen-activated protein kinase kinase 1 (MEK1)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway regulates fundamental malignant cell processes and contains multiple proto-oncogenes, being a novel target for the treatment of new cancer therapies (Barbosa, Acevedo, & Marmorstein, 2020). In hepatocellular carcinoma espe- cially MEK/ERK signaling cascade is activated by AMPK, resulting in a reduction of ERK1/2 phosphorylation levels in tissues (Yuan, Dong, Yap, & Hu, 2020).
Quercetin was associated with alterations in the Akt/mTOR and MEK1/ERK1/2 signaling pathways in in vitro and in vivo models of the preferred systematic review and meta-analysis (PRISMA) of anti- tumor effects in hepatocarcinoma associated with alteration of several pathways, Akt/mTOR and MEK1/ERK1/2 signaling routes (Fern´andez-Palanca et al., 2019). Quercetin inhibited the tryptic rennin-like activity of proteases by inhibiting the MEK1/ERK1/2 sig- naling pathway in hepatocellular carcinoma HepG2 cells and activated p38 MAPK and JNK phosphorylation (L. Wu et al., 2019). Quercetin regulated apoptosis, migration, invasion, and autophagy to inhibit hepatocellular carcinoma by, which also connected with the JAK2/ STAT3 signaling pathway in LM3 cells (Hosui et al., 2009). And quercetin enhanced liver fibrosis and HCC formation and activated STAT3, which was regulated by TGF-β in mice (Yu, Zhu, Riedlinger, Kang, & Hennighausen, 2012). We found that after treatment with quercetin 15 days with the induction of preneoplastic lesions, quercetin reversed the number of preneoplastic lesions and their regions and downregulated EGFR expression and regu- lated this signaling pathway, In addition, quercetin affected the phosphorylation status of Src-1, STAT5, and transcription factor- specific protein 1 (Sp1), and the normal status of the liver was also confirmed by IGF-1 expression is confirmed by the restora- tion of expression in rats (Carrasco-Torres et al., 2017). More- over, NQ also inactivated the Akt and ERK1/2 signaling pathways (K. W. Ren et al., 2017).

5.3 | Notch

Activation of Notch signaling pathway can promote cell proliferation, regulate cell cycle, and inhibit apoptosis, and so forth. Notch1 is an unfavorable prognostic biomarker in HCC patients (Viatour et al., 2011; J. N. Zhu et al., 2017) and can impede the invasion and migration of hepatocellular carcinoma tumor cells by regulating the interaction of Cox2/Snail/E-cadherin (Huang et al., 2016) or PTEN with FAK genes (L. Li et al., 2017), thus promoting hepatocarcinogenesis, invasion, and metastasis.
Quercetin inhibited CK2α and downregulates Notch1 and Gli2 mRNA and protein expression in hepatocellular carcinoma in rats (Salama, El-Karef, El Gayyar, & Abdel-Rahman, 2019), and the ability of quercetin to target Notch and Hedgehog signaling was associated with the development of hepatocellular carcinoma in thioacetamide- fed male SD rats (Guan et al., 2016).

5.4 | Wnt/β-catenin

The Wnt/β-catenin signaling pathway regulates tumor progression by promoting cell proliferation and cell migration, and its aberrant activa- tion is associated with hepatocarcinogenesis (Nusse & Clevers, 2017). The transcription factor β-catenin protein is a crucial component of Wnt/β-catenin, playing a role in the development of early-stage cancer.
Quercetin blocking Wnt/β-catenin signaling reduced the survival and proliferation of B-1 cells in autoimmune diseases and tumor for- mation (Novo et al., 2015) and synergistically with curcumin exerted antiproliferative effects through Wnt/β-catenin and apoptotic signaling pathways in part in A375 cells (Srivastava & Srivastava, 2019). Moreover, quercetin reversed multidrug resistance in HCCs through the FZD7/β-catenin pathway, suggesting that quercetin could be developed as an effective natural antihuman hepatocellular carcinoma sensitizer in hepatocellular carcinoma cells (Z. Chen et al., 2018). The network mechanism of the interaction between Wnt/β-catenin and Notch pathway by quercetin remained to be further studied.

5.5 | PI3K/Akt and NF-κB

The PI3K/Akt signaling pathway is a key pathway regulating cell growth signaling, and activation of the Akt pathway can alter the com- position of fatty acids, promoting the malignant transformation of liver cells, including the growth, proliferation, and metastasis of liver cell cancer cells, thereby inhibiting cell apoptosis and aggravating the occurrence of liver cancer (Khemlina, Ikeda, & Kurzrock, 2017). As the downstream of the PI3K/Akt pathway, NF-κB is involved in the development and progression of cancer (H. Chen et al., 2016). Quercetin inhibited PI3K/Akt and ERK signaling pathways via attenuating apoptosis in HCC and HepG2, activating Bax translocation to the mitochondrial membrane, and decreasing the Bcl-2/Bax ratio (Granado-Serrano, Martín, Bravo, Goya, & Ramos, 2006). Quercetin activated the NF-κB signaling pathway, activated the pro-inflammatory cytokine cyclooxygenase 2 (COX-2), IL-1β mRNA, and suppressed IL-4 mRNA expression (Ahmed, Ahmed, Fahim, & Zaky, 2019). In human hepatoma cells, quercetin also suppressed the expression of ZD55 TRAIL-activated NF-κB and downstream targets IκBα, p65, and p50 (Zou, Zheng, Ge, Wang, & Mou, 2018). In addition, NQ downregulated the rat liver inflammatory mediator MMP-13 and controlled diethylnitrosamine-induced cancer (Mandal et al., 2014). NQ also inhibited COX-2 by inhibiting the nuclear translocation of NF-κB and its binding to COX-2 promoters in wistar male rats (K. W. Ren et al., 2017).

5.6 | Others

The MMPs/TIMPs proteasome system plays an important role in reg- ulating cellular function and maintaining intracellular proteostasis by regulating protein ubiquitination and degrading misfolded or harmful proteins through protein hydrolysis, respectively, and is an attractive target for the treatment of cancer (Tsukamoto, 2016). Moreover, both MMPs and TIMPs are involved in tissue remodeling and decisively regulate tumor cell processes, including tumor angiogenesis.
Quercetin inhibited cell cycle stagnation in most hepatoma cell lines, but the stasis period varies from cell line to cell line (Hisaka et al., 2020). The relationship between the incidence of autophagy and tumorigenic progression has been extensively studied (L. Liu, Liao, He, & Li, 2017). Autophagy deficiency is associated with clinicopatho- logical features and poor outcome in hepatocellular carcinoma (Allaire, Rautou, Codogno, & Lotersztajn, 2019). Stimulation of tumor cell autophagy may be one of the effective means of treating hepatocellu- lar carcinoma. mTOR is involved in tumor development (Guri et al., 2017), and persistent mTORC1 inhibition also induces inflam- mation while enhancing tumorigenesis (Ferrín, Guerrero, Amado, Rodríguez-Per´alvarez, & De la Mata, 2020). In cancer cells, activation of Nrf2 confers survival and growth advantages (Chio et al., 2016; Rojo de la Vega, Chapman, & Zhang, 2018; Todoric et al., 2017).
After quercetin treatment, the expression of LC3, a typical bio- marker of autophagy, was significantly upregulated, whereas the expression of P62 was dose- and time-dependent (Wu et al., 2019). And quercetin was able to inhibit metabolic activity and cell death through apoptosis in HCC cell lines such as HepG2, HuH7, and Hep3B2 (Brito et al., 2016), reduced lipid peroxidation, activated cystatin 3 and 9, and promoted enzymatic and nonenzymatic antioxi- dant defense systems to reduce the number of initiating cancer cells. In hepatocellular carcinoma, NQ also significantly upregulated apopto- sis, further studies showed that NQ accelerated the lysis of caspase-9 and Caspase-3 and induced the release of cytochrome C, thereby pro- moting the apoptosis of HCCs (K. W. Ren et al., 2017). The pathogenesis of liver cancer is complex, and the signaling pathways involved are diverse. The data from experiments with ani- mal models and cell cultures as described above have implicated that the possible mechanisms of liver cancer may be related to hTERT, MEK1/ERK1/2, Notch, Wnt/β-catenin, oxidative stress signaling path- way PI3K/Akt, and inflammatory NF-κB pathway (Figure 6, Table 3).

6 | TOXICITY OF QUERCETIN

Quercetin supplements are commercially available in the United States and Europe, and beneficial effects of quercetin supplements have been reported in clinical trials. In vivo studies indicated that quercetin is not carcinogenic, and no evidence of carcinogenicity associated with oral administration of quercetin was observed in chronic rodent tests (Okamoto, 2005; Utesch et al., 2008). However, several in vivo studies reported on the carcinogenic effects of querce- tin and examined the effects of quercetin on cultured human normal cells, revealing the potential toxicity of quercetin’s presence (Matsuo, Sasaki, Saga, & Kaneko, 2005). However, the method used in the study was unusual, and the result was not reproduced. Therefore, fur- ther clinical studies are needed afterward, in order to ensure safer drug use.

7 | PHARMACOKINETIC STUDY OF QUERCETIN

The pharmacokinetics of quercetin have been studied in animal models and in humans (Table 4). One report investigated the pharma- cokinetic study characteristics of intravenous quercetin in cancer patients at doses of 60–2,000 mg/m2, and quercetin pharmacokinet- ics were described by a first-order two-compartment model with a median T(1/2)alpha of 6 min and median T(1/2)beta of 43 min (Ferry et al., 1996). A study has since examined the pharmacokinetic proper- ties of 8, 20, and 50 mg of quercetin glycosides administered orally to healthy participants and demonstrated that quercetin peak concentration (Cmax) and time to peak (Tmax) were 2.3 ± 1.5 μg/ml and 0.7 ± 0.3 hr (Erlund et al., 2000). Quercetin is found in foods as a variety of glycosides, a pharmacokinetic study in healthy volunteers (eight females and eight males) of a mixture of apple powder (AP) and onion powder (OP) concentrated, while in applesauce (MP) showed higher bioavailability (J. Lee & Mitchell, 2012). In rats, beagles, and pigs and ruminant rumen-free cows, the absolute bioavailability of quercetin (the fraction of the ingested compound that reached the body circula- tion) was only 5% (X. Chen et al., 2005), 4% (Reinboth et al., 2010), <1% (Ader et al., 2000), and 0.1% (Berger et al., 2012), which can be find that there are significant differences in the bioavailability of quer- cetin among different models. When changing the dosage form of quercetin, its bioavailability is altered. Quercetin is a lipophilic compound that is thought to be well absorbed by simple diffusion across the intestinal membrane, but it is ingested primarily as a glycoside, which is converted to a glycoside ligand in the intestine then released by absorption into the intestinal epithelium through the action of β-glycosidase, and both intestinal and oral bacteria (Walle, Browning, Steed, Reed, & Walle, 2005) are involved in this enzymatic hydrolysis, and in fact reports show poor oral bioavailability of single doses (Luca et al., 2020). The poor aque- ous solubility of quercetin (~1 mg/ml in water, ~5.5 mg/ml in simu- lated gastric fluid, and ~28.9 mg/ml in simulated intestinal fluid) and its instability in physiological media have limited its application in pharmacology (Fasolo, Schwingel, Holzschuh, Bassani, & Teixeira, 2007). Therefore, the development of new dosage forms of quercetin with higher solubility and bioavailability is essential, and cocrystallization has recently attracted attention, with co- crystallization is superior to monomeric quercetin, with a nearly 10-fold increase in bioavailability, and the ability to overcome the water insolubility of quercetin (Smith et al., 2011). The apparent water solubility in quercetin-loaded lipid nanocapsules (LNC) was increased by 100-fold (Barras et al., 2009). The bioavailability of quercetin con- taining poly (n-butyl cyanoacrylate) nanoparticles (PBCA NPs) was increased by 2.38-fold and then 4.93-fold after coating with polysor- bate 80 (P-80) (Bagad & Khan, 2015). In nanoprecipitation (NP) and high-pressure homogenization (HPH) methods, poorly water-soluble quercetin-loaded nanosuspensions (QT-NS) were prepared with approximately 70-fold solubility of crude quercetin (M. Sun et al., 2010). The relative bioavailability of quercetin-loaded solid lipid nanoparticles (QT-SLNs) to quercetin suspension was 571.4%, and both Tmax and MRT of quercetin in plasma were delayed as oral deliv- ery carrier to enhance the absorption value of poorly water-soluble quercetin (H. Li et al., 2009). Quercetin nanodrop formulation signifi- cantly improves the pharmacokinetics of the drug (Chang et al., 2015). The quercetin-containing self-nanoemulsifying drug delivery system (Q-SNEDDS) form oil-in-water nanoemulsions in situ to improve the oral bioavailability of quercetin (Tran, Guo, Song, Bruno, & Lu, 2014). Kale et al (Kale, Saraf, Juvekar, & Tayade, 2006) prepared quercetin cyclodextrin solid inclusion complexes and studied the inclusion behavior of quercetin on sulfobutyl ether-7-cyclodextrin (SBE7betaCD), the solubility, and dissolution rate of quercetin were significantly increased after complexation, and the solubility of quer- cetin in polymeric micelles (PMs) was also significantly increased and had high stability in aqueous media (Patra et al., 2018). Thus, with the advancement of modern technology, inclusion complexes (cyclodextrin, micelles), pre-drugs, nanocrystals, emulsions, liposomes, and polymeric nanoparticles (PNs) are other promising novel drug delivery routes. It is believed that more and more new dos- age forms can be used to improve the bioavailability and solubility of quercetin, but the safety has not been examined enough for clinical applications. 8 | CONCLUSION Quercetin is an effective hepatoprotective agent, and its pharmacological effects in liver diseases have been extensively studied, mainly through inhibiting liver inflammation mainly through NF-κB/ TLR/NLRP3 signaling, reducing PI3K/Nrf2-mediated oxidative stress, mTOR activation in autophagy, and inhibiting the expression of apoptotic factor expression associated with the development of liver diseases, showing corresponding efficacy and different in the hepatic steatosis stage, it mainly regulates PPAR, UCP, and PLIN2-related factors to induce fatty browning and inhibits fat accumulation; in the liver fibrosis stage, it mainly affects TGF1β, ERs and apoptosis to inhibit stromal ECM deposition; in the final hepatocellular carcinoma stage, it mainly affects hTERT, MEK1/ ERK1/2, Notch and Wnt/β-catenin-related signaling pathways to inhibit the proliferation and spread of cancer cells. 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