As the metabolic center of the body, the liver plays a vital role in glucose metabolism, lipid metabolism, bile secretion and vitamin storage hormone synthesis (1,2). Consequently, this leads to its constant exposure to potentially pathogenic molecules or endotoxins produced by digestive products and gut microbiota. Moreover, the liver is the target of most hepatotoxic drugs and hepatitis viruses (3), which makes it highly susceptible to damage that can induce different types of liver diseases. Epidemiological reports indicate that >2 million individuals die annually worldwide from liver diseases (4). Although medicines are already available for the treatment of various common liver diseases such as acute liver injury, fatty liver, liver fibrosis and hepatocellular carcinoma (HCC), they usually induce serious adverse effects during treatment. For instance, obeticholic acid, a drug for treating liver fibrosis, can cause itching, while sorafenib, a drug for treating liver cancer, can cause diarrhea (5,6). Therefore, it is urgent to explore safer medicines with fewer side-effects for the treatment of liver diseases.

Traditional Chinese medicine (TCM) has received increasing attention from researchers in the treatment of liver diseases due to its high efficiency, multi-targeting and low side effects. As a monomer of TCM, myricetin (3,3′,4′,5,5′,7-hexahydroxyflavone) is a natural polyhydroxy flavonoid extracted from various plants (7). It has a good safety profile for consumption, as well as being an important ingredient in food and juice drinks (8,9). The US Food and Drug Administration has approved myricetin as being a healthy product (10). Recent studies have revealed that myricetin plays a vital role in the treatment of liver diseases (11,12). Given its edible safety and low side-effects, myricetin is probably a promising candidate for the treatment of liver diseases. However, a review of the efficacy and mechanism of myricetin in the treatment of various liver diseases has not been made, to the best of the authors' knowledge. In view of this, the present study summarized the progress of research on myricetin in the treatment of liver diseases to provide a direction and basis for further exploration of the potential of myricetin in the clinical treatment of liver diseases.

Myricetin, initially extracted from the bark of Myrica nagi by Perkin and Hummel, is widely present in a variety of plants, such as Rosa canina L. (Rose Hip), Urtica dioica L. (Nettle) and Portulaca oleracea L. (Purslane) (13,14). The structural formula of myricetin is shown in Fig. 1. Its relative molecular mass is 318.24 and its melting point is within the range of 324.0–325.5°C. It is soluble in methanol, ethanol and ethyl acetate, slightly soluble in water and insoluble in chloroform and petroleum ether (15). It has been found that berries, vegetables and tea also contain myricetin and there are two main methods to obtain myricetin, namely plant extraction and chemical synthesis (16,17). Moreover, myricetin possesses multiple biological characteristics such as anti-bacterial, anti-inflammatory, anti-oxidant, anti-tumour and immunomodulatory effects (18–20). In view of this, the present study focused on the efficacy and mechanism of myricetin in liver diseases.

Acute liver injury is a liver dysfunction disease with rapid onset, complex causative factors and significant clinical symptoms. As the major component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS) is an important virulence factor inducing acute liver injury (21). It can be recognized and bound by the Toll-like receptor (TLR) 4, which activates the NF-κB signalling pathway to induce an inflammatory response (22). Inactive NF-κB will bind to IκB and remain in the cytoplasm, but when NF-κB in the conjugate is activated, the two become phosphorylated and separate (23). Subsequently, phosphorylated (p-)NF-κB is translocated to the nucleus, thereby inducing the expression of immune-associated factors such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), IL-6, TNF-α and IL-1β (24). Notably, Berköz et al (25) found that myricetin inhibits the expression of p-NF-κB and p-IκB, as well as the inflammation-associated factors COX-2, iNOS, IL-6, TNF-α and IL-1β in a rat model of LPS-induced acute liver injury (Fig. 2). As members of the MAPK cascade system family, ERK, JNK and P38 play essential roles in acute liver injury (26). D-galactosamine (D-GalN), a chemical hepatotoxic agent, is often combined with LPS for the study of acute liver injury. Unexpectedly, Lv et al (27) found that myricetin inhibits the expression of TLR4, p-IκB and MAPK members (p-ERK, p-JNK and p-P38) in LPS/D-GalN-induced acute liver injury, thereby attenuating inflammation-induced liver injury (Fig. 2).

In addition, LPS/D-GalN disrupts the mitochondrial structure of hepatocytes and generates large amounts of reactive oxygen species (ROS), thereby inducing oxidative stress (28). Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) is an important regulatory pathway for liver oxidative stress, in which HO-1 degrades heme and releases biliverdin, CO and ferrous ions to alleviate liver oxidative stress (29). Excessive ROS in hepatocytes induces Nrf2 into the nucleus, promoting the expression of the downstream anti-oxidant gene HO-1 (30). In acute liver injury, myricetin with strong anti-oxidant and free radical scavenging ability promotes the expression of Nrf2 and Ho-1 to alleviate liver oxidative stress injury (Fig. 2) (20,27). Excessive ROS induces the expression and phosphorylation of P53 in hepatocytes (31). P53 promotes the expression of Bax (a pro-apoptotic gene) and inhibits the expression of Bcl-2 (an anti-apoptotic gene), which induces an increase in mitochondrial membrane permeability, resulting in the release of pro-apoptotic factors, such as cytochrome c, from the mitochondria into the cytoplasm (32). In the cytoplasm, cytochrome c forms an apoptotic complex with apoptotic protease-activating factor-1, which activates caspase-9 and caspase-3, thereby triggering the mitochondrial apoptotic pathway and leading to aberrant apoptosis in hepatocytes (33). Lv et al (27) found that myricetin reduces the protein expression of activated caspase-3 (cleaved caspase-3) and caspase-9 (cleaved caspase-9) to inhibit aberrant apoptosis in acute liver injury (Fig. 2). In addition, caspase-3 activates endonucleases in apoptosis, cleaving nuclear DNA and inducing DNA damage (34). STAT3 is involved in DNA damage repair and its phosphorylation (p-STAT3) promotes the expression of FOXM1, which initiates the expression of proteins involved in the regulation of the DNA damage repair system (35). Significantly, Matić et al (36) found that myricetin promotes the expression of p-STAT3 and p-Akt to inhibit DNA damage in pyrogallol-induced acute liver injury (Fig. 2).

Fatty liver disease is a metabolic disease characterized by hepatocellular steatosis, which mainly consists of non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). With the change of the lifestyle and dietary structure of an individual, the incidence of fatty liver disease has shown a significant growing trend and has become a major threat to health in recent years. It has been found that myricetin not only relieves acute liver injury but also plays a vital role in treating AFLD and NAFLD (37,38).

Liver fibrosis is usually recognized as the pathological process of massive synthesis and sustained accumulation of extracellular matrix (ECM) following chronic liver injury. The activation process of hepatic stellate cells (HSCs) expressing α-smooth muscle actin (α-SMA) and producing large amounts of ECM is considered as the key link in the development of liver fibrosis (64). TGF-β1 is the most potent HSC activator. During HSC activation, first, TGF-β1 binds to the type II TGF-β receptors (TβRII), recruiting type I TGF-β receptors (TβRI) to form the TGF-β1/TβRII/TβRI complex (65). Then, the complex generated in the previous step induces a conformational change in TGF-β1R, which promotes the binding of Smad2 to Smad3 and phosphorylation to form the p-Smad2/p-Smad3 complex (66). Finally, the complex generated in the previous step binds to either α-SMA of the nucleus or DNA of connective tissue growth factor, regulating their expression to promote the activation of HSCs (67). Notably, myricetin inhibits the expression of TGF-β1, p-Smad2, p-Smad3 and α-SMA in the livers of mice infected with S. japonicum, thereby alleviating the development of liver fibrosis (Fig. 4) (68).

In addition, platelet-derived growth factor (PDGF) secreted by platelets promotes the activation of HSCs and the deposition of ECM, contributing to the development of liver fibrosis. PDGF-BB promotes the activation and proliferation of HSCs by activating PI3K/Akt and Ras-ERK signaling pathways via promoting the expression of p-AKT and p-ERK in CFSC-8 cells (rat hepatic stellate cells) cells (69). Geng et al (70) found that myricetin reverses the PDGF-BB-induced increase in the expression of p-AKT and p-ERK and decreases the expression of α-SMA and collagen type I (Collagen I) in CFSC-8 cells (Fig. 4). Similarly, myricetin inhibits the expression of liver TGF-β1 and α-SMA in the Ccl4-induced mouse liver fibrosis model, thereby alleviating liver fibrosis (Fig. 4) (71).

HCC is one of the most common cancers worldwide. The signalling pathways that regulate its occurrence and formation have become the focus of researchers' attention in recent years. The hippo signalling pathway controls liver tumorigenesis by regulating the balance between cell proliferation and apoptosis. In HCC, inactivation of the hippo signalling pathway promotes the entry of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif into the nucleus, leading to the abnormal proliferation of HCC cells (72). Myricetin alleviates the development of HCC by inhibiting cell proliferation and promoting apoptosis (Fig. 5) (73). Mechanistically, myricetin promotes the phosphorylation of large tumor suppressor 1/2 to degrade YAP protein and reduce its nuclear translocation (73). This leads to a decrease in the expression of proliferation-promoting genes and an increase in the expression of anti-apoptotic genes in HCC cells (73). As a serine/threonine protein kinase, p21-activated kinase 1 (PAK1) activates the β-catenin signalling pathway to promote the proliferation of cancer cells and inhibit their apoptosis (74). Myricetin inhibits the expression of PKA1 and β-catenin in the diethylinitrosamine-induced rat HCC model, contributing to decreased proliferation and increased apoptosis of HCC cells (75).

Mitochondria are double-membrane organelles that play an important role in cellular energy production, metabolism and signal transduction. The liver, as a major metabolic organ, is rich in mitochondria. Mitochondrial dysfunction in hepatocytes leads to an abnormal increase in ROS, which promotes the activation of oncogenes, inducing the development of HCC (28,76). Moreover, ROS can promote oxidative stress in the liver, causing telomere shortening and chromosomal abnormalities and inducing the transformation of normal hepatocytes into HCC cells (77). However, Chandel and Tuveson (78) found that high levels of ROS can also promote apoptosis and necrosis in HCC cells, thus inhibiting the development of HCC. Analogously, Seydi et al (79) found that myricetin can target mitochondria and increase ROS levels and caspase-3 activity in HCC cells, thereby promoting apoptosis of HCC cells (Fig. 5). Briefly, myricetin inhibits the development of liver cancer by regulating the proliferation and apoptosis of HCC cells.

As the main constituent of medicinal and edible bayberry, myricetin possesses biological characteristics such as anti-tumour, anti-oxidation, anti-inflammatory and anti-bacterial properties (18–20). In liver diseases, the mechanisms of myricetin's action on different types of liver diseases show diversity. However, these mechanisms still cannot fully explain the role of myricetin in various liver diseases and the specific molecular mechanisms need to be further explored. Although a large number of studies have confirmed that myricetin notably improves various liver diseases, this is only at the stage of animal or cellular experiments. To date, clinical trials with myricetin for the treatment of liver diseases have not yet been conducted. Therefore, the future work on myricetin in liver diseases needs to be more invested in clinical research. In addition, the stability of myricetin is limited, which leads to its lower bioavailability. Therefore, future research on the pharmaceutical dosage form of myricetin should be intensified to improve its bioavailability

As a monomer of TCM, myricetin is generally considered to be a safe drug. Yang et al (80) found no side effects in mice treated with 1,000 mg/kg of myricetin. In addition, human umbilical vein endothelial cells did not show significant cytotoxicity following treatment with myricetin (81). However, Canada et al (82) found that the cellular activity of isolated guinea pig intestinal cells was reduced and significant cellular damage occurred following treatment with myricetin. There are also those who consider that myricetin is capable of autoxidation, potentially leading to the development of oxidative stress (83). Therefore, there is an urgent need to further investigate the potential toxicity mechanisms of myricetin.

As a common disease, liver disease has become a serious threat to the health and lives of individuals all over the world. Although there are a wide variety of medications available for the treatment of liver diseases, they all possess significant side-effects and their efficacy remains unsatisfactory. Given the obvious advantages of TCM in research and development cost and therapeutic efficacy, the treatment of liver diseases with TCM has gradually been increasingly accepted and emphasized by researchers in recent years. The present study discussed the effectiveness and mechanism of myricetin in acute liver injury, fatty liver, liver fibrosis and HCC, which can facilitate further research on therapeutic drugs for liver diseases (Table I). It is hoped that the present review will draw the attention of liver disease research scholars to TCM.