- Review Letter
- Open Access
Quercetin as a JAK–STAT inhibitor: a potential role in solid tumors and neurodegenerative diseases
Cellular & Molecular Biology Letters volume 27, Article number: 60 (2022)
The Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway is involved in many immunological processes, including cell growth, proliferation, differentiation, apoptosis, and inflammatory responses. Some of these processes can contribute to cancer progression and neurodegeneration. Owing to the complexity of this pathway and its potential crosstalk with alternative pathways, monotherapy as targeted therapy has usually limited long-term efficacy. Currently, the majority of JAK–STAT-targeting drugs are still at preclinical stages. Meanwhile, a variety of plant polyphenols, especially quercetin, exert their inhibitory effects on the JAK–STAT pathway through known and unknown mechanisms. Quercetin has shown prominent inhibitory effects on the JAK–STAT pathway in terms of anti-inflammatory and antitumor activity, as well as control of neurodegenerative diseases. This review discusses the pharmacological effects of quercetin on the JAK–STAT signaling pathway in solid tumors and neurodegenerative diseases.
Given their highly potent therapeutic activity, fewer side effects, and cost-effectiveness, natural products may be promising candidates for pharmaceutical development as anticancer, anti-autoimmunity, and anti-allergic agents. There is a family of natural compounds called flavonoids that are found widely in flowers and fruits in the form of benzo-gamma-pyrone derivatives. Quercetin is one of these natural products . Quercetin (3,3′,4′,5,7-pentahydroxyflavone) represents the most abundant flavonoid in human diets and can be found at high concentrations in apples, onions, red wine, red grapes, tea (Camelia sinensis), capers, broccoli, lovage, and a wide range of berries [2, 3]. Various cancer cell types, including liver cancer, have been shown to be affected by antineoplastic activity of quercetin via its influence on proliferation, differentiation, and apoptosis . Additionally, quercetin downregulates multiple signal transduction pathways, including NF-κB, MEK–ERK, PI3K–Akt–mTOR, Wnt–β-catenin, and Nrf2–keap1, which contribute to inflammation and carcinogenesis processes [5,6,7]. However, the pleiotropic properties of quercetin warrant further study of other proteins that might also be involved in its mechanisms of action.
JAK–STAT signaling pathway
The Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway exerts an important role in transducing signals from cell membrane receptors to the nucleus [8, 9]. The JAK family of tyrosine kinases bind to the cytoplasmic regions of type I and type II cytokine receptors. The binding of ligands to receptors results in the multimerization of receptors. Some receptor subunits are expressed as homodimers, such as growth hormone and erythropoietin, while others are expressed as heteromultimers such as interleukins (ILs) and interferons (IFNs). Receptors associated with JAKs are activated to start transphosphorylation of JAKs and subsequent recruitment of STATs. Human JAK family has four members: JAK1, JAK2, JAK3, and TYK2 [8, 10]. JAK family members have several distinct domains, including N-terminal FERM domain, Src homology 2 (SH2) domain, pseudokinase domain, and conserved PTK domain . STAT is one of the most prominent transcriptional factor families in cancers, consisting of seven structurally similar members: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6 [11, 12]. Generally, STAT family members contain six common functional domains: a coiled-coil domain (CCD), an N-terminal domain (NH2), a DNA-binding domain (DBD), an SRC homology 2 domain (SH2), a linker domain, and a transactivation domain (TAD). Aberrant activation of the JAK–STAT pathway is evident in various diseases such as cancers  and neurodegenerative diseases . In many cancers, STAT3 is constitutively activated. There are multiple original studies on this issue investigating the role of STAT3 signaling in several solid tumors .
Quercetin properties: structure and biologic functions
Quercetin, also known as 2,3,4,5,7-pentahydroxyflavone or 2,3,4,5,7-dihydroxyphenyl-3,5,7-trihydroxychromen-4-one, contains two benzene rings, A and B, that are connected by a pyrone ring. Owing to the presence of two antioxidant pharmacophores in quercetin’s structure, it can effectively neutralize free radicals and join transitional metal ions. Furthermore, catechol, in conjunction with the OH group present at position C3 in the structure of quercetin, is a highly effective way to scavenge free radicals. As a pentalhydroxyl flavonol, hydroxyl groups of quercetin are positioned on the 3rd, 30th, 40th, and 7th carbon positions in the flavonol structure. Interestingly, with the replacement of diverse functional groups, quercetin becomes more biochemically and pharmacologically active [15,16,17]. Some studies suggest that quercetin is present in two forms: as a standalone compound and as an aglycone or as a mixture with other compounds. In addition to carbohydrates, lipids, alcohols, and sulfate groups, it can be reacted with other molecules to produce numerous derivatives of quercetin, including glycosides, ethers, prenylated quercetins, and sulfated derivatives . Quercetin glycoside is the most abundant flavonoid compound in propolis as well as many other dietary supplements, including fruits and vegetables, such as onions, broccoli, apple, tea, and red wine . Aside from acting as an anticancer, antitumor, anti-ulcer, anti-allergy, antiviral, anti-inflammatory, and antidiabetes agent, it also exerts gastroprotection, antihypertension, immune modulation, and anti-infection effects . A preclinical study demonstrated that quercetin significantly reduced levels of inflammation moderators, including NO synthase, COX-2, and CRP, in a human hepatocyte-derived cell line . Studies conducted on rats have shown that quercetin (80 mg equivalent dose) inhibits acute and chronic inflammation and that it also has significant anti-arthritic properties against adjuvant-induced arthritis [20, 21]. This bioactive compound has also been studied for its anticancer properties. Quercetin is believed to inhibit cancers of various solid tissues, such as breast, lung, nasopharyngeal, kidney, colorectal, prostate, pancreatic, and ovarian cancers, as well as neurodegenerative diseases . In this regard, quercetin is not harmful to healthy cells, while it can impose cytotoxic effects on cancer cells through a variety of mechanisms, making it an effective supplementary agent for treating solid tumors and neurodegenerative diseases in combination with other anticancer medications . Despite the range of biological benefits mentioned above, quercetin has been restricted in its pharmaceutical application as a result of its low hydrosolubility, lack of stability in physiology, high metabolism in the liver prior to reaching the bloodstream, and low bioavailability [23, 24].
In patients with cancer, quercetin was intravenously injected at a dose of 60–2000 mg/m2. The researchers determined a safe dose to be 945 mg/m2. A toxic dose resulted in vomiting, high blood pressure, nephrotoxicity, and a decrease in serum potassium. In intravenous administration, quercetin has a half-life of 0.7–7.8 min. Dispensation content is 3.7 L/m2, and elution is 0.84 L/min/m2 . At a dose of 200 mg, Graefe and colleagues investigated the pharmacokinetics of quercetin. Quercetin has been reported to have a Cmax and a Tmax of 2.3–1.5 g/mL and 0.7–0.3 h, respectively . According to these observations, numerous quercetin analogs and nanoconjugates of quercetin containing various delivery systems have been demonstrated, including liposomes, silver nanoparticles, poly lactic-co-glycolic acid (PLGA), and polymeric micelles, for example, DOX-conjugated micelles, metal-conjugated micelles, nucleic-acid-conjugated micelles, and antibody-conjugated micelles, which show a variety of biological implications such as biphasic, inotropic impacts [27, 28]. For instance, Iacopetta et al. synthesized a series of quercetin derivatives referred to as Q2–Q9 using catechol ketal as the starting material in which the OH groups were all or partially replaced with hydrophobic functional groups such as acetyl esters, ethyl or benzyl ethers, or diphenyl ketals of the catechol system. By inhibiting topoisomerases I and II and modulating intracellular reactive oxygen species (ROS) production, these chemical modifications produced compounds with higher anticancer activity relative to the canonical quercetin in two breast cancer models. Accordingly, quercetin exerts its antioxidant effects via competitive inhibition of the enzyme xanthine oxidase and noncompetitive inhibition of the enzyme xanthine dehydrogenase .
In addition, a study by Guan and colleagues prepared and evaluated quercetin nanoparticles (QPTN) as a means of improving the solubility of quercetin with PLGA and TPGS. The results demonstrated that QPTN was capable of inducing HepG2 cell apoptosis in a dose-dependent way and suppressing tumor growth by 59.07% .
JAK–STAT inhibitory effects of quercetin on cancer
The specific effect of quercetin on tumor cells without any impact on normal or nontransformed cells has compelled many researchers to explore its potential use as an adjuvant in suppressing proliferation, metastasis, epithelial–mesenchymal transition (EMT), and oxidative stress [31,32,33]. Having more potent antitumor activity, fewer side effects, and cost-effectiveness, natural products are promising candidates for pharmaceutical development as anticancer agents. Recently, studies reported that the expression of antiviral genes, such as 2′-5′-oligoadenylate synthetase (2′5′-OAS) and RNA-activated protein kinase (PKR), are stimulated by type-I IFNs through the JAK–STAT pathway [34,35,36]. Although the exact mechanism of action on the JAK–STAT pathway remains unclear, tofacitinib and ruxolitinib are JAK inhibitors that have been approved by the Food and Drug Administration (FDA) for their inhibitory effect on some lymphoma tumor cells. High doses of these drugs cause side effects despite their “pan-JAK” inhibitory effects, including infections and malignant tumors, gastrointestinal perforation, venous thromboembolism, dyslipidemia, and other complications . Patients with rheumatoid arthritis taking tofacitinib, the first JAK inhibitor on the market, have suffered pulmonary thrombosis and death due to high doses of the drug. On the other hand, studies have shown that quercetin increased type-I IFN-induced JAK–STAT signaling through the inhibition of SHP2. It was reported that quercetin has a synergistic effect when concomitantly using some anticancer drugs . According to Tiwari et al., an investigation compared quercetin and gefitinib loaded onto polyvinylpyrrolidone (PVP)-functionalized graphene oxide (GO-PVP) with quercetin and gefitinib separated by polyvinylpyrrolidone (PVP)-functionalized graphene oxide. The combined drugs loaded onto the GO-PVP nano platform were significantly more toxic than the individual drugs loaded onto the platform, as well as the free drugs, in regard to PA-1 cells . Here, we described antitumor effects of quercetin by targeting JAK–STAT signaling pathways (Fig. 1).
Moreover, we suggest that more investigations based on natural products are needed to provide a promising therapeutic approach to enhance the efficacy of anticancer therapy (e.g., chemotherapy, radiotherapy, or radiochemotherapy) in a less toxic manner, also before or after tumor surgery.
Glioblastoma multiforme (GBM) is a malignant tumor of connective tissue, and has been known as the most deadly primary brain tumor [1, 39,40,41]. Flavonoids such as quercetin are able to cross the blood–brain barrier (BBB) via different mechanisms, including carrier-mediated transcellular transport transcellular diffusion or paracellular distribution via tight junctions between BBB endothelial cells [1, 42]. In gliomagenesis, STAT3 may act as an oncogene . Consequently, inflammatory microenvironments may favor tumor development . A potential role for quercetin in the prevention and treatment of glioblastoma has been demonstrated as a suppressor of the STAT3 activation signaling pathway stimulated by IL-6 [44, 45]. In this line, IL-6-induced JAK–STAT3, Rb phosphorylation, cyclin D1 expression, and MMP-2 secretion are inhibited by 48 h treatment with 25 µM quercetin in T98G and U87 GBM cell lines .
On the other hand, mouse peritoneal macrophages were isolated and quercetin was used to treat the ex vivo inflammation induced by lipopolysaccharide in a study by Liao et al. There was a significant decrease in TNF-αTNF-α gene expression levels as well as pro-/anti-inflammatory ratios (TNF-α/IL-10) and inactivation of inflammatory macrophages, but IL-10 gene expression levels were elevated in quercetin-treated macrophages. This suggests that quercetin treatment has overall anti-inflammatory potential. In the activated inflammatory macrophages, quercetin inhibited TLR2 gene expression as well as STAT3 protein phosphorylation . Moreover, as a potential prognostic marker for glioblastoma multiforme (GBM), Axl plays a crucial role. Signals downstream of it include those from NF-κB, JAK–STAT, and PI3K–Akt–mTOR . With 0, 25, 50, and 100 µM doses of quercetin, dose-dependent apoptosis was observed in two GBM cell lines, U87MG and U373MG, resulting from decreased Axl protein expression, IL-6 expression levels, and STAT3 phosphorylation . Furthermore, it was found that quercetin inhibited glioblastoma cell invasion and angiogenesis in vitro. It is possible that quercetin inhibits migration and angiogenesis via downregulating the levels of VEGFA, MMP9, and MMP2 .
Moreover, a previously conducted study synthesized an anticancer drug commonly used in treating glioblastoma that combined nanoquercetin (nanohydrogels) with temozolomide to enhance its specificity and efficacy. As a codelivery vehicle for temozolomide and quercetin, the nanohydrogel facilitated the internalization and cytotoxicity of quercetin. In addition, using quercetin-containing nanohydrogels significantly reduced IL-8 production, IL-6 production, and VEGF production in a dose-dependent manner in pro-inflammatory conditions, with meaningful implications for glioblastoma cells’ drug resistance. However, it was used at 100 and 200 µg doses .
Recent evidence suggests that supplementation of standard therapy with quercetin enhances the efficacy of treatment of experimental glioblastoma by inducing apoptosis through caspase-3 and PARP-1 cleavage, and suppressing PI3K–Akt activation. When combining quercetin and irradiation, the breakdown of caspase-3, PARP-1, phosphorylated ERK, JNK, p38, and RAF1 were increased, whereas phosphorylated Akt was considerably decreased. By enhancing apoptosis through inducing caspase-3 and PARP-1 cleavage and suppressing activation of the Akt pathway, quercetin supplements standard therapy with improved efficacy in treating experimental glioblastoma .
Quercetin also induces apoptosis in human glioblastoma multiform T98G cells, which is associated with activation of caspase 3 and 9 and release of cytochrome C from the mitochondria. It has been suggested that apoptosis is initiated by stress in the endoplasmic reticulum by increasing expression of caspase 12 and the presence of multiple granules in the cytoplasm upon temozolomide treatment with or without quercetin .
Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is the second and sixth leading cause of cancer-related death in men and women, respectively . It is estimated that 600,000–800,000 new cases of HCC occur annually on a global level . Various intracellular signaling pathways activation implicated in cell growth, survival, apoptosis, angiogenesis, and differentiation have been found to facilitate HCC development and progression. These oncogenic signaling pathways include JAK–STAT, PI3K–Akt–mTOR, Wnt–β-catenin, and Ras–Raf–MAPK pathways . According to recent investigations, the signal transducer and activator of transcription protein 1 (STAT1) was phosphorylated by quercetin, promoting endogenous IFN-α-regulated gene expression. Additionally, quercetin reduced the proliferation rate of hepatocellular carcinoma HepG2 and Huh7 cells when IFN-α expression was stimulated . In the development of HCC, STAT3 is generally accepted as an oncogene. Activation of STAT3 stimulates the expression of several genes that play a significant role in cancer development, emphasizing the importance of STAT3 in HCC . Wu et al.’s study revealed that quercetin suppresses hepatocellular carcinoma progression via modulating cellular invasion, migration, and autophagy. Moreover, its effect may partly be attributed to the downregulation of the JAK2–STAT3 signaling pathway . Also, quercetin plays a suppressive role against HCC cells through apoptosis and p16-mediated cell cycle arrest, and its combination with cisplatin displayed synergistic inhibitory activity in triggering apoptosis and suppressing cancer cell growth . A microprecipitation high-pressure homogenization technique, with methyl polyethylene glycol-Deoxycholic acid (mPEG-DCA) as a stabilizer, was used to synthesize three quercetin nanosuspensions containing different particle sizes. All three quercetin nanoparticles (QUR-NPs) were found to have significantly stronger inhibitory activity against MCF-7 cells and hepatocyte 7702 cells in vitro, while inhibiting tumors against the murine hepatic carcinoma H22 model in vivo .
The effects of quercetin on in vivo and in vitro hepatocellular carcinoma progression were also examined in a study using LM3 and nude mouse tumor models, in which quercetin suppressed cell apoptosis, migration, invasion, and autophagy by inhibiting the JAK2–STAT3 signaling pathway .
Despite declines in incidence rates, increased awareness, and advances in treatment strategies, gastric cancer remains one of the most prevalent forms of cancer worldwide . The development and progression of gastric cancer are influenced by Helicobacter pylori infection, lifestyle factors, dietary factors, and various genetic aberrations [60, 61]. Upon entry into human gastric epithelial cells, the CagA protein of H. pylori may exhibit tyrosine phosphorylation with downstream effects on signal transduction. Researchers have found that the CagA phosphorylation status affects the signal switch between the JAK–STAT3 and SHP2–ERK pathways via gp130, elucidating a novel mechanism for the H. pylori signaling pathway [62, 63].
Furthermore, González-Segovia et al. found that oral quercetin administration reduced H. pylori infection and both inflammatory response and lipid peroxidation in vivo . Quercetin inhibits the proliferation of human gastric cancer (GC) MGC-803 cells. This may be related to the downregulation of leptin and leptin receptor protein, leptin mRNA, and leptin receptor mRNA expression by the JAK–STAT pathway . Also, combined treatment with quercetin and curcumin was observed with substantial inhibition of cell proliferation, associated with loss of mitochondrial membrane potential (ΔΨm), cytochrome C release, and decreased ERK and AKT phosphorylation. These findings suggest that the combination of quercetin and curcumin leads to apoptosis through the mitochondrial pathway .
Women worldwide are most likely to develop breast cancer with a high rate of mortality [67, 68]. Despite improvements in chemotherapeutic agents, new strategies to overcome tumor cell survival remain elusive despite progress in understanding the mechanisms of chemoresistance [69, 70].
To create an ideal cancer treatment protocol, we need to identify key target molecules, as well as safe and stable delivery systems that will allow us to overcome resistance and minimize the side effects of chemotherapeutic agents [71, 72].
In this regard, Safi et al. indicated that concomitantly using docetaxel and quercetin synergistically results in inhibition of both cell growth and cell survival, as well as apoptosis induction in MDA-MB-231 human breast cancer cell line . The results showed that single-agent treatment with docetaxel or quercetin leads to a decrease in the viability of the MDA-MB-231 cells at 48 h, whereas the combination of docetaxel (7 nM) and quercetin (95 μM) displayed the greatest synergistic effects with a combination index value of 0.76 accompanied by enhancing expression of the p53 gene as well as pro-apoptotic protein BAX, and reducing the expression of STAT3 anti-apoptotic protein BCL2, phosphorylated AKT, and ERK1/2 . Further, quercetin has been revealed to have a role in antiproliferation of HER2-overexpressing BT-474 BC cells via STAT3 signaling suppression and caspase-dependent extrinsic apoptosis activation, while causing an increase in sub-G0/G1 apoptotic population .
Pancreatic cancer (PC), a highly fatal disease, is one of the most commonly occurring digestive malignancies. PC is one of the leading causes of cancer-related death worldwide [53, 74, 75]. Moreover, patients with PC have a 5-year survival rate of 21.3% for local-stage cancer, 8.9% for regional-stage cancer, and 1.8% for distant-stage cancer .
According to Yu et al., quercetin inhibited PATU-8988 and PANC-1 cell growth and reduced MMP release. In this study, they examined whether quercetin treatment affected malignancy in cells by activating STAT3 and IL-6. They indicated that, when MMP secretion and EMT occur, STAT-3 signaling is stimulated, and quercetin reverses IL-6-induced EMT and invasion. It has been revealed that quercetin can inhibit EMT, invasion, and metastasis, as well as reverse the IL-6-induced increase in PC cells through inhibiting the STAT3 signaling pathway . Pang et al. found that quercetin hindered PC death by improving fatty acid uptake, enhancing cell adhesion, stimulating the immune system, and increasing thrombospondin-1 activity . Additionally, previous research has indicated that quercetin inhibits BCL-2 protein synthesis and upregulates the p53 gene, suggesting that it has pro-apoptotic effects. However, inhibiting BCL-2 transcription may prevent tumor growth . Nwaeburu et al. found that quercetin treatment induced the expression of microRNA 200b-3p in pancreatic cancer AsPC1 cell lines, which appears to be crucial in regulating Notch signaling and irregular division of pancreatic ductal adenocarcinoma (PDA) cells . Furthermore, it has been found that quercetin suppressed the nuclear translocation and phosphorylation of Smad2 and Smad3. When downstream signaling is stimulated by TGF-β1, Smad2 and Smad3 form heteromeric complexes with Smad4 and translocate to the nucleus, inducing the expression of EMT-inducing transcription factors (EMT-TFs) .
Non-small-cell lung cancer
One of the leading causes of cancer-related death worldwide is non-small-cell lung cancer (NSCLC) . Lung carcinoma can be divided into two subtypes on the basis of morphological and genetic features: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) [82, 83]. NSCLC accounts for 80–85% of all lung carcinoma cases [84, 85].
Several molecules, including flavonoids, have been found to be beneficial in treating NSCLC. Several cancers have already been reported to be prevented by quercetin, including lung cancer [86, 87]. According to Mukherjee et al.’s study, in NSCLC with constitutive IL6–STAT3 activation for uncontrolled cell proliferation, targeted blockade of NF-κB and IL-6–STAT3 signaling by quercetin (66 µM of quercetin for 12, 18, 24, 36, and 48 h) represents an innovative approach for treating NSCLC. Through inhibition of IL-6–STAT3 signaling pathways, particularly those involved in NF-κB activation, the Bcl2–Bax imbalance can then trigger the cancer cell to undergo self-destruction by triggering apoptosis . These observations may provide valuable information for the potential application of quercetin in NSCLC prevention/therapy.
In recent years, there have been numerous developments regarding the JAK–STAT inhibitory effects of quercetin in other types of cancer. For instance, compared with docetaxel alone, quercetin increased inhibition of PI3K–Akt and the STAT3 signaling pathways in androgen-dependent prostate cancer cells, and decreased expression of the multidrug-resistance-related protein. At a concentration of 5 µM, quercetin also significantly enhanced cell cycle arrest at G2/M phase and sensitivity to chemotherapy in LAPC-4-AI and PC-3 prostate cancer cells [88,89,90,91].
Moreover, the pretreatment of ovarian cancer with quercetin significantly increased the cytotoxicity of cisplatin and activated the stress response of the three branches of the endoplasmic reticulum . Further, it inhibited STAT3, resulting in the downregulation of the BCL-2 gene downstream of STAT3, and improved the antitumor effect of cisplatin in a mouse xenograft model for ovarian cancer [93,94,95].
In response to EGCG, STAT1 and STAT3 phosphorylation was reduced dose-dependently. Quercetin and EGCG was synergistic and inhibited cells’ upregulation of inducible nitric oxide synthase (iNOS) and intercellular adhesion molecule-1 (ICAM-1) in response to cytokine-induced iNOS and ICAM-1 levels induced by JAK–STAT activation in cholangiocarcinoma cells. According to recent studies on primary effusion lymphoma (PEL) cells, quercetin inhibits the STAT3 and PI3K/Akt/mTOR pathways, thereby downregulating prosurvival cellular proteins, including cMyc and cyclin D1. Furthermore, quercetin decreased the IL-6 and IL-10 release, resulting in PEL cell death . However, besides numerous studies on anticancer effects of quercetin, there is an information gap on the JAK–STAT inhibitory effects on other cancer types such as colorectal, skin, kidney, thyroid, eye, cervical, blood, and bone cancers that should be investigated.
JAK–STAT inhibitory effects of quercetin on neurodegenerative diseases
There are a number of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), leukodystrophies, and diseases involving neuron and/or glia degeneration . Even though the central nervous system (CNS) was once considered immune-privileged, nowadays we know that T cells continuously patrol the CNS and innate immunity is the first line of defense for the CNS. Demyelination and/or degeneration of neurons are caused by aberrant activation of innate immune cells, which releases pro-inflammatory cytokines, chemokines, ROS, and NO, or polarizes and activates effector T cells and myeloid cells and T cells. The majority of these processes are dependent on JAK–STAT signaling pathways, and a number of neurodegenerative diseases are characterized by inflammation in the CNS, and the JAK–STAT signaling pathway leads to pathogenic inflammation . In this line, by regulating STAT1 signaling, T-helper type 1 (Th1) cells produce cytokines that alter the balance between Th1 and Th2 cells, altering immune function and inflammation. On the other hand, as a result of STAT1 hyperactivation and defective nuclear dephosphorylation, mutations in the STAT1 gene trigger chronic mucocutaneous candidiasis and adversely affect Th1 and Th17 cell responses .
Hence, using natural compounds such as quercetin alone or in combination with other drugs could be used to treat neurodegenerative diseases by decreasing neuroinflammation through the JAK–STAT signaling pathway (Fig. 1). For example, according to a study carried out on C6 glioma cells, nanoliposomes can increase quercetin anticancer activity by inhibiting the JAK2–STAT3 pathway and mitochondrial ROS generation . Additionally, coupling quercetin with nanoparticles, such as β-cyclodextrin-dodecylcarbonate, makes it more readily permeable through the blood–brain barrier, making it an excellent candidate for STAT intervention and neuroinflammatory treatment .
Multiple sclerosis (MS), a chronic neurodegenerative and demyelinating disease that impacts the CNS, is characterized by aggressive lesions throughout the brain and spinal cord. MS affects approximately 2.5 million people worldwide. Affected people are typically between the ages of 20 and 40 years, and the disease prevalence is three times higher among women than among men [100,101,102]. Mirzazadeh et al. studied the effects of quercetin administration (10 mg/kg daily) on the development of disability in rat models of multiple sclerosis. Quercetin therapy led to a better outcome in rats. There was a significant increase in myeloperoxidase activity and nitric oxide levels in the serum of the rat models that were treated with quercetin, as well as in the level of lipid peroxidation in the brain tissue . As documented in another study, quercetin (25 or 50 mg/kg daily for 7 or 14 days) reduced the latency of visual evoked potential (VEP) waves in rats with lysolecithin (LPC)-induced demyelination when ingested orally. In addition, quercetin treatment decreased glial activation in treated animals compared with the control group. Moreover, following LPC injection, quercetin treatment reduced demyelinated areas and led to an increase in remyelination .
According to Muthian et al., by inhibiting IL-12-induced tyrosine phosphorylation of STAT3, STAT4, JAK2, and TYK2, quercetin inhibits the proliferation of T cells and differentiation of Th1. Muthian et al. in this in vitro study suggested that quercetin may be useful in treating MS and other autoimmune diseases caused by Th1 cells by inhibiting IL-12 signaling and Th1 differentiation . In addition, in a recent study, SJL/J mice were treated every other day for 25 days with 50 or 100 µg of quercetin during an experimental autoimmune encephalomyelitis model. Quercetin reduced inflammation in mice compared with control and quercetin-treated mice on many parameters, such as pathological score (CNS demyelination and inflammation), immune system responses toward neural antigens and IL-12, production of splenocytes, macrophages, and microglia, and activation of the JAK–STAT pathway .
Parkinson’s disease (PD) is a neurodegenerative disease characterized by neuroinflammation, oxidative stress, and selective dopaminergic neuronal loss. Therefore, available pharmacotherapy is based on supplying dopamine precursors or on stimulation of dopamine synthesis in the remaining neurons and modulating neuroinflammation and oxidative stress . In comparison with PD-induced controls, quercetin 30 mg/kg was administered for 14 consecutive days to 6-OHDA-intoxicated rats to significantly improve dopamine and antioxidant enzyme levels. Furthermore, the quercetin-treated group exhibited fewer dead neurons. In another study, quercetin doses of 100 and 200 mg/kg were significantly effective in alleviating motor balance and coordination in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the rotarod test . On the other hand, administration of 50 mg/kg of quercetin in rotenone-induced PD in rats led to an improvement in movement, dopamine level, and oxidative balance .
In addition to antioxidant properties, quercetin has anti-inflammatory and neuroprotective roles in PD . Many neurodegenerative disorders, including Parkinson’s disease, are characterized by aberrant activation or phosphorylation of the JAK–STAT signaling pathway. In PD, interferon-gamma (IFN-γ) and IL-6 were found to be two of the most potent activators of the JAK–STAT pathway . Therefore, dysregulation of the JAK–STAT in PD and its involvement in various inflammatory pathways make it a promising PD therapy approach. Accordingly, administration of quercetin with piperine alone and in combination significantly prevented neuroinflammation via reducing the levels of IL-6, TNF-α (two potent activators of the JAK–STAT pathway), and IL-1β in PD in experimental rats .
Alzheimer’s disease (AD) is typically caused by the accumulation of amyloid-β (Aβ) aggregates and hyperphosphorylation of tau proteins, resulting in synaptic dysfunction and neurofibrillary tangles (NFTs). AD accounts for 60–80% of total dementia cases, and it mostly affects the elderly (65 years old or older). AD affects about 35.6 million people worldwide, with 4.6 million newly diagnosed cases reported every year. Also, from 60 years of age, the prevalence of AD doubles every 5 years [111, 112]. The levels of STAT1 protein have been shown to be elevated in both cytosolic and particulate fractions from the cortex of patients with AD in comparison with healthy controls . In the APPswe/PS1dE9 and 3xTg mouse models of AD, STAT3 immunoreactivity has been found to increase in the nucleus of GFAP- and vimentin-immunoreactive astrocytes. Lentivirus-mediated expression of suppressor of cytokine signaling protein 3 (SOCS3), a negative regulator of this pathway, downregulated STAT and inhibited JAK-specific activity, and suppressed nuclear STAT3 immunoreactivity as well as GFAP immunoreactivity in astrocytes, implicating the JAK–STAT3 pathway in astrocytic reaction .
Under certain conditions, Aβ, which is believed to play an important role in this pathology, is neurotoxic. By activating JAK2–STAT3, nicotinic acetylcholine receptors are known to reduce Aβ neurotoxicity, but whether STAT3 gene regulation is required is unknown . It was found that quercetin suppressed the formation and stability of Aβ fibrils. In this line, multiple steps of the formation of sclerotic plaques were inhibited by quercetin suppressing β-secretase (an enzyme engaged in Aβ formation) and aggregation of Aβ [116, 117].
Moreover, Aβ neurotoxicity is prevented by quercetin and its derivatives via activating the JAK2–STAT3 signaling pathway and maintaining cholinergic activity . Quercetin, is also preclinically reported to be neuroprotective in Alzheimer’s disease because of its antioxidant and anti-inflammatory activity. In neuroinflammation, the release of cytokines, such as TNF-α and IL-1β, by astrocytes and microglia is regulated by triggers such as protein aggregation and neuronal death, initiating an immune response. Cytokine release can be reduced by inhibiting the inducible forms of cyclooxygenase (COX-2) and lipoxygenase (LOX) . Quercetin acts as a pro-antioxidant, inhibiting the release of neuroinflammatory mediators such as interleukin-6 (IL-6), IL-1β, COX-2, LOX, and tumor necrosis factor (TNF-α) by oxidative stress [106, 119].
It was also interesting to find that, in a SAMP8 mouse study, the effects of free quercetin (25 mg/kg/day) and nano-encapsulated quercetin particles (25 mg/kg every 2 days) were evaluated. Almost twofold more quercetin was found in the brains of mice treated with quercetin nanoparticles, which resulted in major effects on memory and learning . Moreover, quercetin acts as a pro-antioxidant, inhibiting the release of neuroinflammatory mediators such as interleukin-6 (IL-6, IL-1β) and tumor necrosis factor (TNF-α) by oxidative stress.
Quercetin is now in phase II of a clinical trial to evaluate its safety and feasibility as a senolytic for Alzheimer’s. Researchers chose to conduct the study after demonstrating that a combination of drugs used in the trial prevented neuron death in a mouse model of AD. Further, quercetin and dasatinib are both known to be senolytics, substances that remove senescent cells in a selective manner, therefore playing a role in many age-related or age-predisposed diseases .
Conclusions and future perspectives
Natural polyphenolic compounds like quercetin that inhibit JAK and STAT family members have been found to have fewer side effects and less toxicity. The anti-inflammatory, antiproliferative, and anti-angiogenic activities of quercetin make it an excellent cancer-prevention agent. Consequently, we suggest that quercetin can be used as an effective, safe, and cost-effective JAK/STAT inhibitor alone or concomitantly with other JAK inhibitors for solid tumors and neurodegenerative disease. More investigations are needed to evaluate potential JAK–STAT inhibitory effects of quercetin for other malignancies, as well as neurodegenerative and autoimmune diseases. Although quercetin may exhibit considerable anticancer activity, it has poor solubility in water, low permeability, and high metabolism in the liver before reaching the bloodstream, resulting in low bioavailability. Moreover, Dajas et al. discovered that quercetin oxidization produces quinones that are not reduced by antioxidants such as tocopherol (vitamin E) and ascorbate (vitamin C), leading to increased damage to neurons (neurotoxicity). The findings of the study suggest that modulating kinases restores redox equilibrium and reduces the discomfort of quercetin restriction . Quercetin should undergo further structural modifications to overcome these limitations in order to be more effective against cancer. Quercetin, for example, can be delivered using nanoconjugated molecules, such as liposomes, silver nanoparticles, polylactic acid, or polymeric micelles, such as DOX-conjugated micelles, metal-conjugated micelles, nucleic-acid-conjugated micelles, or antibody-conjugated micelles. Quercetin-conjugated nanoparticles have been cited for a variety of advantages, including their controlled drug release, retention in tumors, and anticancer properties.
Signal transducer and activator of transcription
Vascular endothelial growth factor
Mammalian target of rapamycin
Mitogen-activated protein kinase
Nuclear factor kappa-light-chain-enhancer of activated B cells
Non-small-cell lung cancer
Small-cell lung cancer
Central nervous system
Tavana E, Mollazadeh H, Mohtashami E, Modaresi SMS, Hosseini A, Sabri H, et al. Quercetin: a promising phytochemical for the treatment of glioblastoma multiforme. BioFactors. 2020;46(3):356–66.
Häkkinen SH, Kärenlampi SO, Heinonen IM, Mykkänen HM, Törrönen AR. Content of the flavonols quercetin, myricetin, and kaempferol in 25 edible berries. J Agric Food Chem. 1999;47(6):2274–9.
Bischoff SC. Quercetin: potentials in the prevention and therapy of disease. Curr Opin Clin Nutr Metab Care. 2008;11(6):733–40.
Casella ML, Parody JP, Ceballos MP, Quiroga AD, Ronco MT, Francés DE, et al. Quercetin prevents liver carcinogenesis by inducing cell cycle arrest, decreasing cell proliferation and enhancing apoptosis. Mol Nutr Food Res. 2014;58(2):289–300.
Granado-Serrano AB, Martín MA, Bravo L, Goya L, Ramos S. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J Nutr. 2006;136(11):2715–21.
Igbe I, Shen X-F, Jiao W, Qiang Z, Deng T, Li S, et al. Dietary quercetin potentiates the antiproliferative effect of interferon-α in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase. Oncotarget. 2017;8(69): 113734.
Zalpoor H, Bakhtiyari M, Liaghat M, Nabi-Afjadi M, Ganjalikhani-Hakemi M. Quercetin potential effects against SARS-CoV-2 infection and COVID-19-associated cancer progression by inhibiting mTOR and hypoxia-inducible factor-1α (HIF-1α). Phytother Res. 2022;8:78.
Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M. The role of JAK–STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signaling. 2017;15(1):1–13.
Seif F, Aazami H, Khoshmirsafa M, Kamali M, Mohsenzadegan M, Pornour M, et al. JAK inhibition as a new treatment strategy for patients with COVID-19. Int Arch Allergy Immunol. 2020;181(6):467–75.
Joshi N, Hajizadeh F, Dezfouli EA, Zekiy AO, Afjadi MN, Mousavi SM, et al. Silencing STAT3 enhances sensitivity of cancer cells to doxorubicin and inhibits tumor progression. Life Sci. 2021;275: 119369.
Levy DE, Lee C-K. What does Stat3 do? J Clin Investig. 2002;109(9):1143–8.
Safi A, Heidarian E, Ahmadi R. Quercetin synergistically enhances the anticancer efficacy of docetaxel through induction of apoptosis and modulation of PI3K/AKT, MAPK/ERK, and JAK/STAT3 signaling pathways in MDA-MB-231 breast cancer cell line. Int J Mol Cell Med. 2021;10(1):11.
Brooks AJ, Putoczki T. JAK-STAT Signalling Pathway in Cancer. New York: Multidisciplinary Digital Publishing Institute; 2020.
Yan Z, Gibson SA, Buckley JA, Qin H, Benveniste EN. Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases. Clin Immunol. 2018;189:4–13.
Vafadar A, Shabaninejad Z, Movahedpour A, Fallahi F, Taghavipour M, Ghasemi Y, et al. Quercetin and cancer: new insights into its therapeutic effects on ovarian cancer cells. Cell Biosci. 2020;10(1):1–17.
Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 2008;585(2–3):325–37.
Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci. 2016;5:89.
Lakhanpal P, Rai DK. Quercetin: a versatile flavonoid. Internet J Med Update. 2007;2(2):22–37.
García-Mediavilla V, Crespo I, Collado PS, Esteller A, Sánchez-Campos S, Tuñón MJ, et al. The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur J Pharmacol. 2007;557(2–3):221–9.
Mamani-Matsuda M, Kauss T, Al-Kharrat A, Rambert J, Fawaz F, Thiolat D, et al. Therapeutic and preventive properties of quercetin in experimental arthritis correlate with decreased macrophage inflammatory mediators. Biochem Pharmacol. 2006;72(10):1304–10.
Guardia T, Rotelli AE, Juarez AO, Pelzer LE. Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. Farmaco. 2001;56(9):683–7.
Vargas AJ, Burd R. Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutr Rev. 2010;68(7):418–28.
Sak K. Site-specific anticancer effects of dietary flavonoid quercetin. Nutr Cancer. 2014;66(2):177–93.
Hirpara KV, Aggarwal P, Mukherjee AJ, Joshi N, Burman AC. Quercetin and its derivatives: synthesis, pharmacological uses with special emphasis on anti-tumor properties and prodrug with enhanced bio-availability. Anti-Cancer Agents Med Chem. 2009;9(2):138–61.
Ferry DR, Smith A, Malkhandi J, Fyfe DW, deTakats PG, Anderson D, et al. Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res. 1996;2(4):659–68.
Graefe EU, Wittig J, Mueller S, Riethling AK, Uehleke B, Drewelow B, et al. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J Clin Pharmacol. 2001;41(5):492–9.
Vinayak M, Maurya AK. Quercetin loaded nanoparticles in targeting cancer: recent development. Anti-Cancer Agents Med Chem. 2019;19(13):1560–76.
Iacopetta D, Grande F, Caruso A, Mordocco RA, Plutino MR, Scrivano L, et al. New insights for the use of quercetin analogs in cancer treatment. Future Med Chem. 2017;9(17):2011–28.
Bindoli A, Valente M, Cavallini L. Inhibitory action of quercetin on xanthine oxidase and xanthine dehydrogenase activity. Pharmacol Res Commun. 1985;17(9):831–9.
Guan X, Gao M, Xu H, Zhang C, Liu H, Lv L, et al. Quercetin-loaded poly (lactic-co-glycolic acid)-d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles for the targeted treatment of liver cancer. Drug Delivery. 2016;23(9):3307–18.
Guo Y, Tong Y, Zhu H, Xiao Y, Guo H, Shang L, et al. Quercetin suppresses pancreatic ductal adenocarcinoma progression via inhibition of SHH and TGF-β/Smad signaling pathways. Cell Biol Toxicol. 2021;37(3):479–96.
Asgharian P, Tazehkand AP, Soofiyani SR, Hosseini K, Martorell M, Tarhriz V, et al. Quercetin impact in pancreatic cancer: an overview on its therapeutic effects. Oxid Med Cell Long. 2021;2021:9.
Soofiyani SR, Hosseini K, Forouhandeh H, Ghasemnejad T, Tarhriz V, Asgharian P, et al. Quercetin as a novel therapeutic approach for lymphoma. Oxid Med Cell Long. 2021;2021:88.
Hovanessian AG. On the discovery of interferon-inducible, double-stranded RNA activated enzymes: the 2′–5′ oligoadenylate synthetases and the protein kinase PKR. Cytokine Growth Factor Rev. 2007;18(5–6):351–61.
Nabi-Afjadi M, Karami H, Goudarzi K, Alipourfard I, Bahreini E. The effect of vitamin D, magnesium and zinc supplements on interferon signaling pathways and their relationship to control SARS-CoV-2 infection. Clin Mol Allergy. 2021;19(1):1–10.
Raftery N, Stevenson NJ. Advances in anti-viral immune defence: revealing the importance of the IFN JAK/STAT pathway. Cell Mol Life Sci. 2017;74(14):2525–35.
Reddy V, Cohen S. Jak inhibitors: what is new? Curr Rheumatol Rep. 2020;22(9):1–10.
Tiwari H, Karki N, Pal M, Basak S, Verma RK, Bal R, et al. Functionalized graphene oxide as a nanocarrier for dual drug delivery applications: the synergistic effect of quercetin and gefitinib against ovarian cancer cells. Colloids Surf B. 2019;178:452–9.
Zalpoor H, Shapourian H, Akbari A, Shahveh S, Haghshenas L. Increased neuropilin-1 expression by COVID-19: a possible cause of long-term neurological complications and progression of primary brain tumors. Hum Cell. 2022;909:1–3.
Zalpoor H, Akbari A, Nabi-Afjadi M. Ephrin (Eph) receptor and downstream signaling pathways: a promising potential targeted therapy for COVID-19 and associated cancers and diseases. Hum Cell. 2022;35(3):952–4.
Karami Fath M, Babakhaniyan K, Zokaei M, Yaghoubian A, Akbari S, Khorsandi M, et al. Anti-cancer peptide-based therapeutic strategies in solid tumors. Cell Mol Biol Lett. 2022;27(1):1–26.
Youdim KA, Shukitt-Hale B, Joseph JA. Flavonoids and the brain: interactions at the blood–brain barrier and their physiological effects on the central nervous system. Free Radical Biol Med. 2004;37(11):1683–93.
Zalpoor H, Akbari A, Samei A, Forghaniesfidvajani R, Kamali M, Afzalnia A, et al. The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: inflammasome and JaK inhibitors as potential promising therapies. Cell Mol Biol Lett. 2022;27(1):1–21.
Michaud-Levesque J, Bousquet-Gagnon N, Béliveau R. Quercetin abrogates IL-6/STAT3 signaling and inhibits glioblastoma cell line growth and migration. Exp Cell Res. 2012;318(8):925–35.
Xia T, Li J, Ren X, Liu C, Sun C. Research progress of phenolic compounds regulating IL-6 to exert antitumor effects. Phytother Res. 2021;35(12):6720–34.
Liao Y-R, Lin J-Y. Quercetin modulates cytokine expression and inhibits TLR2 expression and STAT3 activation in mouse activated inflammatory macrophages. J Explor Res Pharmacol. 2020;5(3):31–41.
Davra V, Kumar S, Geng K, Calianese D, Mehta D, Gadiyar V, et al. Axl and Mertk receptors cooperate to promote breast cancer progression by combined oncogenic signaling and evasion of host antitumor immunity. Can Res. 2021;81(3):698–712.
Kim HI, Lee SJ, Choi Y-J, Kim MJ, Kim TY, Ko S-G. Quercetin induces apoptosis in glioblastoma cells by suppressing Axl/IL-6/STAT3 signaling pathway. Am J Chin Med. 2021;49(03):767–84.
Liu Y, Tang Z-G, Yang J-Q, Zhou Y, Meng L-H, Wang H, et al. Low concentration of quercetin antagonizes the invasion and angiogenesis of human glioblastoma U251 cells. Onco Targets Ther. 2017;10:4023.
Barbarisi M, Iaffaioli RV, Armenia E, Schiavo L, De Sena G, Tafuto S, et al. Novel nanohydrogel of hyaluronic acid loaded with quercetin alone and in combination with temozolomide as new therapeutic tool, CD44 targeted based, of glioblastoma multiforme. J Cell Physiol. 2018;233(10):6550–64.
Pozsgai E, Bellyei S, Cseh A, Boronkai A, Racz B, Szabo A, et al. Quercetin increases the efficacy of glioblastoma treatment compared to standard chemoradiotherapy by the suppression of PI-3–kinase–Akt pathway. Nutr Cancer. 2013;65(7):1059–66.
Jakubowicz-Gil J, Langner E, Bądziul D, Wertel I, Rzeski W. Silencing of Hsp27 and Hsp72 in glioma cells as a tool for programmed cell death induction upon temozolomide and quercetin treatment. Toxicol Appl Pharmacol. 2013;273(3):580–9.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2018;68(6):394–424.
Hin Tang JJ, Hao Thng DK, Lim JJ, Toh TB. JAK/STAT signaling in hepatocellular carcinoma. Hepatic Oncol. 2020;7(1):HEP18.
Alqahtani A, Khan Z, Alloghbi A, SaidAhmed T, Ashraf M, Hammouda D. Hepatocellular carcinoma: molecular mechanisms and targeted therapies. Medicina. 2019;55(9):526.
Wu L, Li J, Liu T, Li S, Feng J, Yu Q, et al. Quercetin shows anti-tumor effect in hepatocellular carcinoma LM3 cells by abrogating JAK2/STAT3 signaling pathway. Cancer Med. 2019;8(10):4806–20.
Zhao J-l, Zhao J, Jiao H-J. Synergistic growth-suppressive effects of quercetin and cisplatin on HepG2 human hepatocellular carcinoma cells. Appl Biochem Biotechnol. 2014;172(2):784–91.
Qiao Y, Cao Y, Yu K, Zong L, Pu X. Preparation and antitumor evaluation of quercetin nanosuspensions with synergistic efficacy and regulating immunity. Int J Pharm. 2020;589: 119830.
Eyvazi S, Khamaneh AM, Tarhriz V, Bandehpour M, Hejazi MS, Sadat ATE, et al. CpG islands methylation analysis of CDH11, EphA5, and HS3ST2 genes in gastric adenocarcinoma patients. J Gastrointest Cancer. 2020;51(2):579–83.
Khanna P, Chua PJ, Bay BH, Baeg GH. The JAK/STAT signaling cascade in gastric carcinoma. Int J Oncol. 2015;47(5):1617–26.
Beheshtirouy S, Eyvazi S, Tarhriz V. Evaluation of Mutations in 23S rRNA, rdxA and frxA genes of Helicobacter pylori in paraffin-embedded gastric biopsy specimens from Iranian gastric cancer and gastritis patients. J Gastrointest Cancer. 2021;52(1):207–11.
Song Y, Zhao M, Zhang H, Yu B. Double-edged roles of protein tyrosine phosphatase SHP2 in cancer and its inhibitors in clinical trials. Pharmacol Ther. 2021;56:107966.
Yang E, Chua W, Ng W, Roberts TL. Peripheral cytokine levels as a prognostic indicator in gastric cancer: a review of existing literature. Biomedicines. 2021;9(12):1916.
González-Segovia R, Quintanar JL, Salinas E, Ceballos-Salazar R, Aviles-Jiménez F, Torres-López J. Effect of the flavonoid quercetin on inflammation and lipid peroxidation induced by Helicobacter pylori in gastric mucosa of guinea pig. J Gastroenterol. 2008;43(6):441–7.
Qin Y, He L, Chen Y, Wang W, Zhao X, Wu M. Quercetin affects leptin and its receptor in human gastric cancer MGC-803 cells and JAK-STAT pathway. Chin J Cell Mol Immunol. 2012;28(1):12–6.
Zhang J-Y, Lin M-T, Zhou M-J, Yi T, Tang Y-N, Tang S-L, et al. Combinational treatment of curcumin and quercetin against gastric cancer MGC-803 cells in vitro. Molecules. 2015;20(6):11524–34.
Sohrabi E, Moslemi M, Rezaie E, Nafissi N, Khaledi M, Afkhami H, et al. The tissue expression of MCT3, MCT8, and MCT9 genes in women with breast cancer. Genes Genomics. 2021;43(9):1065–77.
Moslemi M, Moradi Y, Dehghanbanadaki H, Afkhami H, Khaledi M, Sedighimehr N, et al. The association between ATM variants and risk of breast cancer: a systematic review and meta-analysis. BMC Cancer. 2021;21(1):1–12.
Gatti L, Zunino F. Overview of tumor cell chemoresistance mechanisms. Chemosensitivity. 2005. p. 127–48.
Fodale V, Pierobon M, Liotta L, Petricoin E. Mechanism of cell adaptation: when and how do cancer cells develop chemoresistance? Cancer J (Sudbury, Mass). 2011;17(2):89.
Cengiz E, Karaca B, Kucukzeybek Y, Gorumlu G, Gul MK, Erten C, et al. Overcoming drug resistance in hormone-and drug-refractory prostate cancer cell line, PC-3 by docetaxel and gossypol combination. Mol Biol Rep. 2010;37(3):1269–77.
Brannon-Peppas L, Blanchette JO. Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev. 2004;56(11):1649–59.
Srinivasan A, Thangavel C, Liu Y, Shoyele S, Den RB, Selvakumar P, et al. Quercetin regulates β-catenin signaling and reduces the migration of triple negative breast cancer. Mol Carcinog. 2016;55(5):743–56.
Li J, Song Y, Zhang C, Wang R, Hua L, Guo Y, et al. TMEM43 promotes pancreatic cancer progression by stabilizing PRPF3 and regulating RAP2B/ERK axis. Cell Mol Biol Lett. 2022;27(1):1–19.
Li W, Wu L, Jia H, Lin Z, Zhong R, Li Y, et al. The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression. Cell Mol Biol Lett. 2021;26(1):1–20.
Simard EP, Ward EM, Siegel R, Jemal A. Cancers with increasing incidence trends in the United States: 1999 through 2008. Cancer J Clin. 2012;62(2):118–28.
Yu D, Ye T, Xiang Y, Shi Z, Zhang J, Lou B, et al. Quercetin inhibits epithelial–mesenchymal transition, decreases invasiveness and metastasis, and reverses IL-6 induced epithelial–mesenchymal transition, expression of MMP by inhibiting STAT3 signaling in pancreatic cancer cells. Onco Targets Ther. 2017;10:4719.
Pang B, Xu X, Lu Y, Jin H, Yang R, Jiang C, et al. Prediction of new targets and mechanisms for quercetin in the treatment of pancreatic cancer, colon cancer, and rectal cancer. Food Funct. 2019;10(9):5339–49.
Davoodvandi A, Shabani Varkani M, Clark CC, Jafarnejad S. Quercetin as an anticancer agent: focus on esophageal cancer. J Food Biochem. 2020;44(9): e13374.
Nwaeburu CC, Abukiwan A, Zhao Z, Herr I. Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer. Mol Cancer. 2017;16(1):1–10.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.
Liu Y, Huang R, Xie D, Lin X, Zheng L. ZNF674-AS1 antagonizes miR-423-3p to induce G0/G1 cell cycle arrest in non-small cell lung cancer cells. Cell Mol Biol Lett. 2021;26(1):1–14.
Xu S, Zhang H, Wang A, Ma Y, Gan Y, Li G. Silibinin suppresses epithelial–mesenchymal transition in human non-small cell lung cancer cells by restraining RHBDD1. Cell Mol Biol Lett. 2020;25(1):1–12.
Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24(14):2137–50.
Liao M, Peng L. MiR-206 may suppress non-small lung cancer metastasis by targeting CORO1C. Cell Mol Biol Lett. 2020;25(1):1–13.
Youn H, Jeong J-C, Jeong YS, Kim E-J, Um S-J. Quercetin potentiates apoptosis by inhibiting nuclear factor-kappaB signaling in H460 lung cancer cells. Biol Pharm Bull. 2013;36(6):944–51.
Mukherjee A, Khuda-Bukhsh AR. Quercetin down-regulates IL-6/STAT-3 signals to induce mitochondrial-mediated apoptosis in a nonsmall-cell lung-cancer cell line, A549. J Pharmacopuncture. 2015;18(1):19.
Wang P, Henning SM, Heber D, Vadgama JV. Sensitization to docetaxel in prostate cancer cells by green tea and quercetin. J Nutr Biochem. 2015;26(4):408–15.
Wang P, Phan T, Gordon D, Chung S, Henning SM, Vadgama JV. Arctigenin in combination with quercetin synergistically enhances the antiproliferative effect in prostate cancer cells. Mol Nutr Food Res. 2015;59(2):250–61.
Rauf A, Imran M, Khan IA, Rehman M, Gilani SA, Mehmood Z, et al. Anticancer potential of quercetin: a comprehensive review. Phytother Res. 2018;32(11):2109–30.
Maleki Dana P, Sadoughi F, Asemi Z, Yousefi B. The role of polyphenols in overcoming cancer drug resistance: a comprehensive review. Cell Mol Biol Lett. 2022;27(1):1–26.
Long Q, Xie Y, Huang Y, Wu Q, Zhang H, Xiong S, et al. Induction of apoptosis and inhibition of angiogenesis by PEGylated liposomal quercetin in both cisplatin-sensitive and cisplatin-resistant ovarian cancers. J Biomed Nanotechnol. 2013;9(6):965–75.
Liu Y, Gong W, Yang Z, Zhou X, Gong C, Zhang T, et al. Quercetin induces protective autophagy and apoptosis through ER stress via the p-STAT3/Bcl-2 axis in ovarian cancer. Apoptosis. 2017;22(4):544–57.
Granato M, Rizzello C, Montani MSG, Cuomo L, Vitillo M, Santarelli R, et al. Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways. J Nutr Biochem. 2017;41:124–36.
Arzuman L, Beale P, Chan C, Yu JQ, Huq F. Synergism from combinations of tris (benzimidazole) monochloroplatinum (II) chloride with capsaicin, quercetin, curcumin and cisplatin in human ovarian cancer cell lines. Anticancer Res. 2014;34(10):5453–64.
Senggunprai L, Kukongviriyapan V, Prawan A, Kukongviriyapan U. Quercetin and EGCG exhibit chemopreventive effects in cholangiocarcinoma cells via suppression of JAK/STAT signaling pathway. Phytother Res. 2014;28(6):841–8.
Nicolas CS, Amici M, Bortolotto ZA, Doherty A, Csaba Z, Fafouri A, et al. The role of JAK–STAT signaling within the CNS. JAK-STAT. 2013;2(1): e22925.
Jain M, Singh MK, Shyam H, Mishra A, Kumar S, Kumar A, et al. Role of JAK/STAT in the neuroinflammation and its association with neurological disorders. Ann Neurosci. 2022:09727531211070532.
Ghosh A, Sarkar S, Mandal AK, Das N. Neuroprotective role of nanoencapsulated quercetin in combating ischemia–reperfusion induced neuronal damage in young and aged rats. PLoS ONE. 2013;8(4): e57735.
Lassmann H, Van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8(11):647–56.
Bayat P, Farshchi M, Yousefian M, Mahmoudi M, Yazdian-Robati R. Flavonoids, the compounds with anti-inflammatory and immunomodulatory properties, as promising tools in multiple sclerosis (MS) therapy: a systematic review of preclinical evidence. Int Immunopharmacol. 2021;95: 107562.
Mirmosayyeb O, Naderi M, Raeisi S, Ebrahimi N, Ghaffary EM, Afshari-Safavi A, et al. Hearing loss among patients with multiple sclerosis (PwMS): a systematic review and meta-analysis. Multiple Sclerosis Relat Disord. 2022;89:103754.
Mirzazadeh E, Khezri S, Abtahi Froushani SM. Effects of quercetin on improving the damage caused by free radicals in the rat models of multiple sclerosis. ISMJ. 2019;22(1):1–15.
Naeimi R, Baradaran S, Ashrafpour M, Moghadamnia AA, Ghasemi-Kasman M. Querectin improves myelin repair of optic chiasm in lyolecithin-induced focal demyelination model. Biomed Pharmacother. 2018;101:485–93.
Muthian G, Bright JJ. Quercetin, a flavonoid phytoestrogen, ameliorates experimental allergic encephalomyelitis by blocking IL-12 signaling through JAK–STAT pathway in T lymphocyte. J Clin Immunol. 2004;24(5):542–52.
Wróbel-Biedrawa D, Grabowska K, Galanty A, Sobolewska D, Podolak I. A flavonoid on the brain: quercetin as a potential therapeutic agent in central nervous system disorders. Life. 2022;12(4):591.
Lv C, Hong T, Yang Z, Zhang Y, Wang L, Dong M, et al. Effect of quercetin in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced mouse model of Parkinson’s disease. Evid-Based Complement Altern Med. 2012;2012:8.
El-Horany HE, El-latif RNA, ElBatsh MM, Emam MN. Ameliorative effect of quercetin on neurochemical and behavioral deficits in rotenone rat model of Parkinson’s disease: modulating autophagy (quercetin on experimental Parkinson’s disease). J Biochem Mol Toxicol. 2016;30(7):360–9.
Sharma S, Raj K, Singh S. Neuroprotective effect of quercetin in combination with piperine against rotenone-and iron supplement-induced Parkinson’s disease in experimental rats. Neurotox Res. 2020;37(1):198–209.
Lashgari N-A, Roudsari NM, Momtaz S, Sathyapalan T, Abdolghaffari AH, Sahebkar A. The involvement of JAK/STAT signaling pathway in the treatment of Parkinson’s disease. J Neuroimmunol. 2021;89:577758.
Khan H, Ullah H, Aschner M, Cheang WS, Akkol EK. Neuroprotective effects of quercetin in Alzheimer’s disease. Biomolecules. 2020;10(1):59.
Nishino T, Oshika T, Kyan M, Konishi H. Effect of the glycine-rich domain in GAREM2 on its unique subcellular localization upon EGF stimulation. Cell Mol Biol Lett. 2021;26(1):1–11.
Kitamura Y, Shimohama S, Ota T, Matsuoka Y, Nomura Y, Taniguchi T. Alteration of transcription factors NF-κB and STAT1 in Alzheimer’s disease brains. Neurosci Lett. 1997;237(1):17–20.
Haim LB, Ceyzériat K, Carrillo-de Sauvage MA, Aubry F, Auregan G, Guillermier M, et al. The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer’s and Huntington’s diseases. J Neurosci. 2015;35(6):2817–29.
Buckingham SD, Jones AK, Brown LA, Sattelle DB. Nicotinic acetylcholine receptor signalling: roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacol Rev. 2009;61(1):39–61.
Schroeter H, Spencer JP, Rice-Evans C, Williams RJ. Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. Biochem J. 2001;358(3):547–57.
Zaplatic E, Bule M, Shah SZA, Uddin MS, Niaz K. Molecular mechanisms underlying protective role of quercetin in attenuating Alzheimer’s disease. Life Sci. 2019;224:109–19.
Chiba T, Yamada M, Sasabe J, Terashita K, Shimoda M, Matsuoka M, et al. Amyloid-β causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons. Mol Psychiatry. 2009;14(2):206–22.
Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, et al. Quercetin, inflammation and immunity. Nutrients. 2016;8(3):167.
Puerta E, Suárez-Santiago JE, Santos-Magalhães NS, Ramirez MJ, Irache JM. Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer’s disease. Int J Pharm. 2017;517(1–2):50–7.
Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644–58.
Dajas F, Abin-Carriquiry JA, Arredondo F, Blasina F, Echeverry C, Martínez M, et al. Quercetin in brain diseases: potential and limits. Neurochem Int. 2015;89:140–8.
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Zalpoor, H., Nabi-Afjadi, M., Forghaniesfidvajani, R. et al. Quercetin as a JAK–STAT inhibitor: a potential role in solid tumors and neurodegenerative diseases. Cell Mol Biol Lett 27, 60 (2022). https://doi.org/10.1186/s11658-022-00355-3
- JAK–STAT inhibitor
- Solid tumors
- Neurodegenerative diseases