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The liver is an important organ that participates in the body’s chemical composition regulation, among which are detoxification, energy storage, and protein and lipid metabolism activities. These functions are important for metabolic control. Nevertheless, several other causes, including poisoning agents, drugs, and alcohol abuse, among others, might disrupt the structural and functional homeostasis of the liver, resulting in hepatotoxicity. The underlying pathophysiological pathways in this condition are oxidative stress, inflammation, apoptosis, and fibrosis. Plant bioactive compounds have been considered as protective agents for the liver in recent years. Quercetin, a flavonoid polyphenol, is an antioxidant with anti-inflammatory and antifibrotic effects. Several experimental studies have shown that quercetin has the potential to lower oxidative stress by scavenging ROS. It was demonstrated to activate the Nrf2/HO-1 pathway and inhibit the NF-κB-mediated inflammatory response. Additionally, quercetin has been shown to alleviate fibrosis by suppressing the TGF-β1/Smad3 pathway. Quercetin has also been determined to reduce apoptosis, support mitochondrial function, and restore liver enzyme levels to control levels. The poor bioavailability of quercetin limits its pharmacological potential. Therefore, new strategies such as nanoformulations, phospholipid complexes, and combination therapy are being researched to enhance the bioavailability and efficacy of this compound. The present results support the multipotent hepatoprotective potential of quercetin. Quercetin has demonstrated a favorable safety and toxicological profile in both preclinical and clinical settings. Daily doses of up to 1000–1200 mg have been shown to be well-tolerated in humans, with only mild and transient adverse effects reported. More long-term controlled human studies, however, would be needed to assess its clinical effects and side effects. In this chapter, available information on the protective potential of quercetin against liver injury is discussed based on the state of the art and as a basis for future research.
Kamil Ozdag Science Faculty, Department of Biology, Karamanoğlu Mehmetbey University, Karaman, Türkiye
Emine Okumus
Faculty of Engineering, Department of Food Engineering, Van Yüzüncü Yıl University, Van, Türkiye
*Address all correspondence to: matemiz@kmu.edu.tr
1. Introduction
1.1 The physiological importance of the liver and the role of quercetin
The liver is a multifunctional and dynamic organ that plays a central role in maintaining metabolic homeostasis (Figure 1). It has been shown to regulate vital processes such as detoxification, energy production, protein and lipid metabolism, and the storage of substances such as hormones, vitamins, minerals, and iron [1]. In addition, the liver performs a pivotal function in the process of detoxification, whereby it eliminates harmful compounds from the body and prevents toxic effects. Despite its notable capacity for regeneration, this ability is subject to limitations in cases of chronic damage, potentially resulting in severe pathological consequences [2]. Liver injury can be induced by pharmaceutical agents such as paracetamol, fluconazole, amoxicillin, diclofenac, ciprofloxacin, oral contraceptives, chlorpromazine, and antituberculosis drugs. The use of these drugs can lead to the development of various hepatotoxic pathologies, such as fulminant hepatitis, hepatic necrosis, benign neoplasms, or venous obstruction.
Figure 1.
Major physiological functions of the liver.
Liver diseases continue to be one of the leading causes of death and morbidity worldwide. Liver cancer is a significant health concern, occupying the third position in terms of cancer-related mortality and the sixth position in terms of incidence. According to data from 2022, approximately 865,000 new cases of liver cancer were diagnosed worldwide, with 757,948 deaths reported [3]. The five-year relative survival rate for the disease is only 21.7% [4], indicating that liver pathologies pose a serious threat to global public health.
The etiology of liver diseases is multifactorial in nature. Hepatitis B and C viruses are responsible for the development of diseases that result in chronic inflammation and fibrosis by directly damaging hepatocytes. Autoimmune hepatitis is the result of a misdirected immune response of the immune system against liver cells. Furthermore, the long-term consumption of alcohol [5], substance abuse [6], metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called nonalcoholic fatty liver disease (NAFLD), and liver tumors [7] have also been identified as significant pathological causes. Current estimates suggest that approximately 25% of the global population is affected by NAFLD, with projections indicating a potential increase to 56% over the next decade [8, 9]. This increase has the potential to result in a significant escalation in the prevalence of MASLD-related hepatocellular carcinoma, particularly in countries such as China, France, and the United States.
The process of liver damage is multifactorial, with oxidative stress, inflammation, apoptosis, and fibrosis playing a fundamental role in its pathogenesis [10]. Drug-induced liver injury is a clinically significant health problem, leading to hepatocellular damage through mechanisms such as redox imbalance, accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), lipid peroxidation, and mitochondrial dysfunction [11]. One of the best-known examples of this is acetaminophen (paracetamol) toxicity. Acetaminophen is converted to toxic intermediates by the CYP2E1 and CYP1A2 enzymes, which, in turn, cause hepatocyte necrosis as a result of depletion of glutathione stores [12]. Furthermore, toxic compounds such as alcohol, aflatoxin, and carbon tetrachloride (CCl4) are also important agents of liver toxicity [13, 14]. Liver fibrosis is a common pathological consequence of chronic liver damage resulting from viral hepatitis, alcoholism, MASLD, and autoimmune diseases. Characterized by excessive accumulation of fibrous tissue, this condition can progress to cirrhosis and liver failure through progressive structural changes. Furthermore, environmental toxins (e.g., acrylamide, microplastics) and iron overload can contribute to hepatic stress and cell death. Accumulation of microplastics in liver tissue has been associated with inflammation, induction of oxidative stress, and disruption of metabolic homeostasis [15].
In recent years, extensive research has been conducted on natural antioxidants and phytochemicals that potentially treat pathological processes. Among these compounds, quercetin (3,3’,4’,5,7-pentahydroxyflavanone) is a bioflavonoid abundant in fruits, vegetables, and plant products. It is noted for its antioxidant, anti-inflammatory, antifibrotic, anticancer, and immunomodulatory properties [16]. As demonstrated in the study by Ramzan et al. [17], the hydroxyl groups and the 4-oxo functional group present in the molecular structure of quercetin result in high free radical scavenging and metal ion chelating capacity.
Numerous studies conducted in recent years have reported that quercetin exhibits protective effects in conditions such as MASLD, alcoholic liver disease, drug-induced toxicity, and fibrosis [18, 19]. The observed effects of quercetin are attributed to its ability to reduce oxidative stress, suppress the inflammatory response, protect mitochondrial function, and limit fibrogenesis [20, 21]. This section aims to provide a comprehensive review, in line with the current literature, by systematically addressing the biological effects of quercetin, its pharmacological mechanisms, and its therapeutic role in experimental liver disease models.
1.2 Literature search methodology
A comprehensive literature search was conducted to identify peer-reviewed studies addressing the hepatoprotective mechanisms and pharmacological potential of quercetin. Major scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar, were systematically searched for publications between 2010 and 2025. The search strategy combined Medical Subject Headings (MeSH) and free-text keywords with Boolean combinations such as “quercetin” OR “flavonoid” AND (“liver injury” OR “hepatotoxicity” OR “hepatoprotection”) AND (“oxidative stress” OR “inflammation” OR “fibrosis” OR “Nrf2” OR “NF-κB” OR “TGF-β” OR “AMPK” OR “autophagy” OR “nanoparticle formulation”). Studies were included if they (i) investigated quercetin’s antioxidant, anti-inflammatory, antifibrotic, or bioavailability-enhancing effects in liver injury; (ii) reported molecular, biochemical, or histopathological findings from in vitro, in vivo, or clinical models; and (iii) were published in peer-reviewed journals. Review papers providing mechanistic or pharmacokinetic insight were also evaluated. Exclusion criteria comprised studies lacking mechanistic relevance, non-peer-reviewed reports, or unrelated systemic outcomes. Reference lists of key papers were manually screened to capture additional literature. The overall search process adhered to PRISMA guidelines to ensure transparency and reproducibility.
2. The fundamental mechanisms of liver damage: Oxidative stress, inflammation, and fibrosis
Liver damage is a complex pathophysiological process resulting from a combination of different etiological factors. The process under discussion is characterized by the presence of oxidative stress, inflammation, and fibrogenesis (Figure 2). This process disrupts cellular integrity through a range of mechanisms, including lipid peroxidation, protein oxidation, and DNA damage [11].
Figure 2.
The pathophysiological processes of liver damage resulting from different etiological factors.
The initial stage of the process of oxidative stress is the disruption of the redox balance within the mitochondria of hepatocytes. Excessive production of ROS has been demonstrated to result in a depletion of glutathione (GSH), a loss of mitochondrial membrane potential, and a decrease in ATP production [12]. The outcome of this process may ultimately result in apoptosis or necrosis. In this instance, the toxic metabolite NAPQI, formed via CYP2E1, rapidly depletes glutathione stores and triggers hepatocellular necrosis. Inflammation represents a significant secondary mechanism in the progression of liver damage. Oxidative stress-induced NF-κB activation has been demonstrated to increase the production of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. These cytokines have been determined to trigger the activation of Kupffer cells and infiltrating monocytes, thereby creating a chronic inflammatory microenvironment in the liver tissue [2]. In the long term, these inflammatory processes accelerate hepatocyte apoptosis, fibrotic tissue remodeling, and the disruption of the liver’s structural integrity. Fibrosis is defined as a progressive consequence of chronic liver damage. Activation of hepatic stellate cells (HSCs) has been demonstrated to result in excessive accumulation of ECM components, with collagen types I and III being particularly notable. The TGF-β1/Smad3 signaling pathway is the most significant regulator of fibrogenesis. The continuous activation of this pathway has been demonstrated to cause disruption of normal tissue architecture and lead to cirrhosis [10].
The three processes of oxidative stress, inflammation, and fibrosis are the common molecular causes of liver diseases. The dynamic interplay between these factors, characterized by positive and negative feedback loops, contributes to the exacerbation and perpetuation of the damage.
The liver, being an organ with high metabolic activity, is constantly exposed to the production of ROS and RNS. While these molecules contribute to cellular signaling within physiological parameters, their excessive accumulation has been demonstrated to induce lipid peroxidation, protein oxidation, and DNA damage, consequently precipitating hepatocellular dysfunction [11]. In order to prevent these harmful effects, the liver has developed a highly effective endogenous antioxidant defense system. The system under consideration consists of two main components: namely, enzymatic antioxidants (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx)) and nonenzymatic antioxidants (glutathione (GSH), ascorbic acid, tocopherols). SOD catalyzes the conversion of superoxide anions into hydrogen peroxide, while CAT and GPx reduce this peroxide to water. Consequently, intracellular redox balance is maintained [12]. However, in conditions such as drug toxicity, alcohol consumption, viral infections, and fatty liver diseases, the oxidative load exceeds the endogenous defense capacity. In such instances, the inadequacy of antioxidant defense mechanisms gives rise to the accumulation of oxidative stress within hepatocytes, thereby precipitating hepatotoxicity [2]. At this point, plant-derived phytochemicals, especially flavonoids, contribute to the restoration of redox homeostasis by providing exogenous antioxidant support.
Flavonoids have been demonstrated to possess the capacity to neutralize free radicals, chelate metal ions, and inhibit lipid peroxidation due to the hydroxyl groups present within their polyphenolic structures [17]. These compounds have also been observed to increase the expression of antioxidant response genes by activating the Nrf2/Keap1/HO-1 signaling pathway. The nuclear translocation of Nrf2 has been demonstrated to stimulate the synthesis of cytoprotective enzymes, including HO-1, NQO1, and GCLC, thereby rendering cells resistant to oxidative damage [22].
Quercetin has been identified as one of the most potent free radical scavengers within the flavonoid group. The 5,7,3’,4’-tetrahydroxyl and 4-oxo functional groups present in its structure have been shown to confer high redox activity [16]. It has been demonstrated that quercetin possesses the capacity to preserve GSH levels in the presence of oxidative stress, augment the activities of SOD and CAT, and diminish the accumulation of lipid peroxidation products (MDA) [23]. However, the effects of quercetin are not limited to direct radical scavenging; it also stabilizes mitochondrial functions, supports ATP production, and regulates apoptotic signaling pathways. The multifaceted effects of this process are effective in preventing oxidative stress-induced cell death and fibrotic progression in liver tissue.
4. Hepatoprotective mechanisms of action of quercetin
Quercetin has been shown to have a hepatoprotective effect on the liver by regulating fundamental pathophysiological processes such as oxidative stress, inflammation, apoptosis, autophagy, and fibrosis through its multifaceted biological activities (Figure 3).
Figure 3.
Molecular mechanisms of the hepatoprotective effect of quercetin in liver dysfunction.
4.1 Experimental findings
Reduction of oxidative stress: Quercetin has been demonstrated to reduce oxidative damage by suppressing the production of ROS. In models of alcoholic liver disease, the administration of quercetin has been shown to reverse the decrease in GPx, CAT, and SOD activities [23]. In addition, it has been determined that the mTOR-TFEB signaling pathway is modulated, thereby protecting the autophagy process and increasing cellular detoxification capacity. Quercetin also exhibits hepatoprotective effects against toxic compounds such as acrylamide, acrylonitrile, and lead acetate. It contributes to the protection of hepatic functions by reducing oxidative stress, mitochondrial damage, and apoptosis caused by these compounds [24–26].
In MASLD models, quercetin has been demonstrated to suppress lipid accumulation, stabilize mitochondrial function, and reduce ROS accumulation. These effects have been linked to AMPK-mediated autophagy and mitophagy activation [27]. Inhibition of this pathway by AMPK inhibitors (Compound C) or autophagy inhibitors (3-MA, CQ) resulted in the abrogation of the protective effects of quercetin, suggesting a dependence on the AMPK/mitophagy axis.
Anti-inflammatory effect: Quercetin reduces the inflammatory response by inhibiting the NF-κB signaling pathway. In experimental hepatotoxicity models, it has been shown to reduce TNF-α, IL-1β, and IL-6 expression and suppress Kupffer cell activation [22]. It has also been observed to increase the expression of antioxidant and cytoprotective genes by activating the Nrf2/HO-1 pathway. In a different study [28], quercetin administration reduced oxidative stress and lipid peroxidation, restored mitochondrial membrane integrity, and reduced the expression of inflammatory pyroptosis markers (NLRP3, caspase-1, IL-18, IL-1β, GSDMD-N). These findings suggest that quercetin alleviates ethanol-induced hepatic injury by supporting mitochondrial homeostasis via PGC-1α [28].
Antifibrotic effect: Fibrosis is defined as the irreversible stage of liver disease. Quercetin has been demonstrated to reduce fibrogenic gene expression by suppressing HSC activation. This phenomenon is associated with the modulation of the TGF-β1/Smad3 signaling pathway [29]. As demonstrated by Hernández-Ortega et al. [30], the fibrosis index and the activities of hepatic enzymes were found to be significantly reduced by quercetin treatment. Conversely, the study revealed that antioxidant enzyme expression increased.
Protection against metal toxicity: In the CdCl2-induced hepatotoxicity model, the Zn/Quercetin complex suppressed oxidative stress and genotoxicity, normalized liver enzyme levels (ALT, AST, ALP), and preserved histological structure integrity [31]. The findings of this study indicate that metal complexes enhance the antioxidant potential of quercetin.
Chemotherapy-induced hepatotoxicity: In models of toxicity induced by the administration of cyclophosphamide, treatment with quercetin resulted in a reduction in serum levels of ALT, AST, ALP, and MDA, and an increase in GSH levels [32]. These results suggest that quercetin may be considered a protective agent against chemotherapy-induced liver injury.
Herbal combinations and synergistic effects: The combination of quercetin with plant polyphenols has been demonstrated to enhance the protective effect. In a study by Murtaza et al. [33], the combination of the two substances showed a stronger antioxidant effect in a Concanavalin A (Con A)-induced liver injury model compared to the effect of the substances administered separately.
4.2 Clinical findings
A plethora of clinical studies have indicated that quercetin displays promising results in improving liver function, reducing inflammation, and regulating metabolic profiles in humans. In clinical studies on metabolic dysfunction-associated MASLD, quercetin supplementation was found to significantly reduce hepatic enzyme activity.
Prysyazhnyuk and Voloshyn [34] reported a decrease of 37.2 %, 50.4%, and 89 % in serum ALT, AST, and GGT levels, respectively, in MASLD patients administered 500 mg/day of quercetin for 12 weeks. The findings of this study suggest that quercetin has the potential to enhance liver function and systemic lipid metabolism. In a randomized controlled trial conducted by Sotiropoulou et al. [19], 600 mg/day of quercetin significantly reduced the hepatic steatosis index and improved HOMA-IR scores in patients with MASLD. The findings indicate that quercetin reduces liver steatosis by increasing insulin sensitivity. Quercetin supplementation led to a 40% reduction in plasma MDA levels in individuals with chronic alcohol-induced liver dysfunction [18]. In addition, the study found significant increases in GSH levels, as well as in SOD and CAT activities. Collectively, these findings substantiate the clinical efficacy of quercetin in alleviating alcohol-induced oxidative stress. Batiha et al. [35] reported that the combination of quercetin and vitamin C produced a greater reduction in hepatic enzyme levels compared to quercetin alone and more effectively reduced serum inflammatory markers. Observational studies, based on dietary intake, also demonstrate a positive correlation between quercetin consumption and liver health. A number of population-based analyses have been conducted in Europe and Australia, the results of which indicate that individuals with a daily intake of flavonoids amounting to approximately 435 mg/day exhibited a significantly lower incidence of liver enzyme abnormalities [35, 36]. The collective findings suggest a potential for quercetin to play a role in the reduction of oxidative stress, inflammation, and metabolic dysfunction in the context of liver diseases.
5. The absorption, bioavailability, and nanotechnological approaches of quercetin
5.1 Absorption and metabolic transformation
Quercetin is a flavonoid that is rapidly metabolized when ingested orally but has limited systemic bioavailability. In human studies, the absorption rate of quercetin varies between 3–17 percent; in animal models, it is approximately 20 percent [37, 38]. The low absorption rate of quercetin is attributable to three factors: its poor water solubility, its limited passage through the intestinal mucosa, and its rapid metabolic conversion in the liver [39]. The absorption process is accelerated by the hydrolysis of quercetin’s glycosidic bonds, and the resulting aglycone form can be easily absorbed at the colonic level due to its lipophilic structure [40]. However, this process is greatly influenced by factors such as the type of saccharide attached, the attachment site, and gut microbiota activity [41]. Quercetin aglycone has not been detected in human plasma; instead, the presence of conjugate metabolites such as quercetin-3-glucuronide, quercetin-3’-sulfate, and isorhamnetin-3-glucuronide has been demonstrated [42]. Some of these metabolites have been identified as having secondary antioxidant activity and the capacity to reduce oxidative damage.
5.2 Approaches to enhance bioavailability
The low bioavailability of quercetin is a significant factor in limiting its pharmacological efficacy. The low systemic circulation of quercetin results from limited solubility, poor passive diffusion through the intestinal epithelium, and the intensity of first-pass metabolism [43]. The glucuronidation and sulfation processes that quercetin undergoes in the intestinal mucosa cause the free form in plasma to disappear rapidly, hindering the full realization of its therapeutic potential.
The development of carrier systems, nanotechnological platforms, and conjugate structures has been undertaken for the purpose of increasing the bioavailability of quercetin. The objective of these strategies is to enhance the solubility, gastrointestinal stability, and cellular uptake of quercetin (Figure 4). Nanoformulations significantly improve bioavailability by exhibiting higher stability, solubility, and absorption properties compared to classical formulations [44].
Figure 4.
The main nanocarrier systems for quercetin delivery.
Nanotechnological carrier systems: The field of nanotechnology has emerged as a significant source of innovation with regard to targeted delivery and controlled release of drugs [45]. In quercetin formulations prepared with hybrid-hydrogel systems, an 18.61-fold increase in the subplasma concentration curve (AUC) and a 62.08-fold increase in total bioavailability were reported [46]. Quercetin’s self-nanoemulsifying drug delivery systems significantly increased oral solubility [47]. Quercetin loaded with zein nanoparticles increased the bioavailability of native quercetin from 1.9% to 5.9% [48], and LipoMicel delivery systems provided an 8- and 9-fold increase in AUC and Cmax, respectively [49]. As demonstrated in the study by Banik et al. [50], the oral bioavailability of quercetin formulated in poly(lipoic acid) nanoparticles increased to 29%. In a similar manner, mesoporous silica nanoparticles conjugated with folic acid have been shown to enhance the biocompatibility of quercetin, thereby facilitating its targeted release in the liver [51].
Hepatic effects of nano-quercetin: The potential of nanotechnology in liver regeneration and targeted therapy approaches has received increased attention in recent years. For example, directing stem cells to damaged liver regions via magnetic nanoparticles has emerged as an innovative strategy to support tissue regeneration [52]. Furthermore, nano-quercetin formulations have a positive impact on biochemical liver functions and can restore normal liver morphology at the histological level [53].
Magnetic and target-oriented systems: Another potential application of nanotechnology in the field of liver regeneration involves the use of magnetic nanoparticles to guide stem cells to areas of damage [52]. These systems have the potential to accelerate tissue regeneration and restore hepatic function.
Metal complexes: The formation of complexes between quercetin and elements such as zinc (Zn) has been demonstrated to enhance both its antioxidant capacity and its biological stability. Zn/quercetin complexes were found to normalize liver enzymes and reduce oxidative stress in a CdCl2-induced hepatotoxicity model [31].
6. Safety, pharmacological interactions, and toxicological profile
6.1 Safety and dosage ranges
Quercetin is widely regarded as a compound that is generally well-tolerated, exhibiting low toxicity. Clinical studies have demonstrated that the daily ingestion of 200–1200 mg of quercetin is safe for adults [35, 36]. The daily dietary intake of this substance typically ranges from 5 to 100 mg, with onions, apples, tea, broccoli, and grapes being the primary dietary sources.
The most commonly employed doses in clinical studies range from 500 to 1000 mg/day [54]. The principle that “the dose makes the poison” is widely accepted, and low-to-moderate quercetin intake is generally considered safe. However, long-term use at doses > 1000 mg/day has been reported to pose risks of renal dysfunction, mineral imbalances, and drug interactions [55]. The United States Food and Drug Administration (FDA) has classified quercetin as a “Generally Recognized as Safe (GRAS)” compound. Furthermore, based on current data, the International Agency for Research on Cancer (IARC) has classified quercetin as “not classifiable for human carcinogenicity” (Group 3) [56]. This classification indicates that quercetin’s proapoptotic effects do not result in carcinogenicity at clinical levels, thereby ensuring its safety within the context of normal nutrition or short-term supplementation. The potential adverse effects are generally mild and transient and may encompass symptoms such as headaches, gastrointestinal disturbances, and a tingling sensation. In rare cases, long-term use at high doses has been associated with nephrotoxicity or a temporary increase in liver enzymes.
A growing body of preclinical and clinical evidence highlights the dose-dependent and context-specific hepatoprotective actions of quercetin. Comparative data suggest that optimal therapeutic efficacy is achieved within the 400–800 mg/day range in humans, depending on formulation and treatment duration, with doses up to 1000–1200 mg/day being well tolerated for short-term interventions [35, 36, 54, 55]. Recent studies further emphasize that bioavailability-enhanced formulations, such as phospholipid complexes and nanoparticle systems, can significantly improve systemic exposure and hepatic distribution without compromising safety. A summary of the most relevant preclinical and clinical studies investigating quercetin’s hepatoprotective effects, dosing strategies, and pharmacological outcomes is presented in Table 1.
Study type/model
Dosage/concentration
Route of administration
Duration
Key findings
Reference
Ethanol-induced hepatotoxicity (Rats)
50 mg/kg/day oral
Oral
14 days
Decreased AST, ALT, γ-GT, and MDA levels; increased hepatic GSH and IL-10; antioxidant and anti-inflammatory effects.
Summary of key preclinical and clinical studies investigating the hepatoprotective effects, dosage, and therapeutic relevance of quercetin.
Data include preclinical animal models and human studies assessing hepatoprotective efficacy, dosing range, and mechanistic insights of quercetin and its analog formulations.
Current clinical and preclinical evidence indicates that oral quercetin doses between 500 and 1000 mg/day are safe and well-tolerated in adults. Preclinical studies commonly employed 50–100 mg/kg, which corresponds to approximately 400–800 mg/day human equivalent dose. Collectively, these data suggest that a daily dose of 500–1000 mg, preferably in enhanced-bioavailability formulations (e.g., liposomal or nanoparticle-based), may optimize hepatoprotective efficacy while maintaining safety margins.
6.2 Pharmacological interactions and toxicological assessment
Quercetin has a regulatory effect on cytochrome P450 (CYP) enzymes and drug transporter systems. It particularly exhibits inhibitory effects on CYP3A4, CYP2C9, CYP2D6, and the P-glycoprotein (P-gp) system [61]. This effect may reduce the metabolic rate of concomitantly used drugs and increase their plasma concentrations. Additionally, quercetin has the potential for pharmacokinetic interactions when used concomitantly with statins, antidepressants, immunosuppressants, and certain chemotherapeutic agents [62]. It is hypothesized that, due to its chelation properties, there may be a reduction in the absorption of essential elements such as iron and zinc. However, when combined with vitamins C and E, it generates an antioxidant synergy that enhances the reduction of oxidative stress [55].
To date, preclinical toxicology studies have failed to provide unequivocal evidence of quercetin’s potential to act as a genotoxin or mutagen. As demonstrated in the study by Andres et al. [54], even high-dose administration (>2000 mg/kg) in long-term rat and mouse model studies did not result in significant organ damage or mortality. Nevertheless, it is imperative to exercise caution when administering high doses of this substance in a clinical context, as it has the potential to induce renal tubular stress and electrolyte imbalances. Although quercetin’s proapoptotic effects are therapeutically significant in cancerous cells, it has been documented that this effect in normal tissues is reversible and occurs within physiological limits. Consequently, contemporary scientific evidence supports the hypothesis that quercetin does not possess carcinogenic potential but rather exhibits chemopreventive properties [18].
6.3 Comparative perspective of quercetin and established hepatoprotective agents
Numerous hepatoprotective compounds, including silymarin, N-acetylcysteine (NAC), and curcumin, have been widely studied as standard reference agents for liver protection. Recent studies have provided comparative insights into their efficacy, mechanisms, and potential synergistic interactions with quercetin. Silymarin, a mixture of flavonolignans derived from Silybum marianum, remains one of the most established hepatoprotective agents, primarily exerting its effects through antioxidant, membrane-stabilizing, and protein-synthesis-promoting mechanisms. However, its poor bioavailability limits clinical efficacy. According to Jashitha et al. [58], co-administration of quercetin (100 mg/kg) and silymarin (100 mg/kg) significantly enhanced the hepatoprotective response in thioacetamide (TAA)-induced hepatotoxic rats, leading to greater reductions in serum ALT, AST, ALP, and bilirubin compared to silymarin alone. Histopathological improvements confirmed the synergistic relationship, suggesting that quercetin’s P-glycoprotein inhibitory effect and modulation of drug-metabolizing enzymes may enhance silymarin bioavailability and potency. Furthermore, Senthila et al. [63] demonstrated that silymarin–quercetin polymeric nanoparticles improved encapsulation efficiency and hepatocyte targeting, addressing the solubility and absorption challenges of both compounds. These findings collectively position quercetin not only as an independent hepatoprotectant but also as a bioavailability enhancer for silymarin formulations.
NAC acts as a glutathione precursor, effectively counteracting oxidative stress and lipid peroxidation, particularly in acetaminophen-induced liver injury. In a comparative in vitro model of antituberculosis drug-induced hepatotoxicity, Singh et al. [64] showed that NAC, silymarin, and curcumin all improved HepG2 cell viability and mitochondrial integrity by reducing oxidative stress markers. Similarly, Yousef et al. [65] found that quercetin and curcumin were comparable to NAC in mitigating paracetamol-induced hepatic oxidative damage. Both flavonoids normalized liver enzyme levels (ALT, AST, ALP), restored antioxidant enzyme activities (SOD, CAT, GPx), and prevented histopathological necrosis, with curcumin showing a slightly stronger effect, followed closely by quercetin. Notably, quercetin achieved this protection without altering glutathione metabolism directly, suggesting a distinct antioxidant pathway compared to NAC. El-Maddawy et al. [66] confirmed that curcumin and NAC displayed comparable hepatoprotective efficacy in acetaminophen-challenged rats through the preservation of mitochondrial integrity and antioxidant defenses. Nonetheless, quercetin’s superior free radical scavenging potency and metal chelation capacity make it a more versatile compound in conditions characterized by oxidative overload. Dogaru et al. [59] further expanded on this by showing that liposomal curcumin formulations provided significant hepatoprotection in acetaminophen-induced injury models, implying that nanocarrier systems, similar to those applied with quercetin, may overcome bioavailability constraints shared by both agents. Overall, these findings demonstrate that quercetin exerts hepatoprotection through multifaceted mechanisms, rivaling or complementing other established hepatoprotectants. Its synergistic interactions with silymarin, comparable efficacy to NAC, and overlapping antioxidant mechanisms with curcumin suggest that quercetin could serve as both a standalone and adjunctive hepatoprotective agent.
6.4 Critical appraisal of evidence and conflicting findings
Although there is abundant evidence for the hepatoprotective role of quercetin through its antioxidant, anti-inflammatory, and antifibrotic mechanisms, some studies have reported variable or even contradictory results, highlighting the context-dependent pharmacodynamics of the compound. Some reports have shown that the hepatoprotective effects of quercetin are highly dose-dependent, with low-to-moderate doses exerting antioxidant actions, while high concentrations (>100 μM in vitro or > 1000 mg/kg in vivo) may induce pro-oxidant activity, increase mitochondrial ROS, and trigger hepatocyte apoptosis [54, 61]. Such biphasic effects are likely linked to its metal ion-chelating and redox cycling properties, which under certain conditions can generate oxidative intermediates instead of scavenging them. In addition, the interaction potential of quercetin with cytochrome P450 enzymes (particularly CYP3A4 and CYP2E1) introduces variability in pharmacological responses. While this inhibition may protect against xenobiotic-induced hepatotoxicity, it can also potentiate drug accumulation and toxicity when combined with other hepatically metabolized compounds, such as statins or acetaminophen [55, 62]. Some investigations, especially those using acute toxic models (e.g., CCl4 or paracetamol), reported strong hepatoprotection, whereas chronic models of MASLD yielded more modest or inconsistent effects [20, 21]. These inconsistencies may stem from variations in administration route, formulation, and duration of exposure.
Ultimately, synergistic formulations with compounds like silymarin or curcumin have demonstrated enhanced protective outcomes; however, antagonistic interactions have also been noted when certain antioxidant systems become oversaturated, potentially leading to reductive stress and impaired signaling through physiological ROS pathways [59].
It is imperative that clinical and preclinical studies conducted on quercetin be evaluated not only for scientific validity but also for compliance with ethical standards. In this context, obtaining informed consent from participants, protecting data confidentiality, and fair selection of participants are fundamental ethical principles in all studies. To protect public health and ensure the credibility of scientific studies regarding the use of quercetin-containing supplements, measures should be implemented in the marketing process to prevent the dissemination of misleading health claims. Research and manufacturing institutions are required to cooperate with regulatory authorities (e.g., FDA and EFSA) to document the compliance of quercetin products with standard quality, safety, and efficacy criteria. Furthermore, the implementation of ethical labeling, clear dosage statements, and improved adverse reaction reporting systems is expected to provide greater transparency in the field of phytotherapeutic products.
7.2 Future research directions
A priority focus of future research should be to improve the limited bioavailability of quercetin. Comprehensive studies of the pharmacokinetic properties of new formulations will provide critical information for dosage optimization and route of administration, paving the way for more effective quercetin-based therapies. Clinical trials can increase the generalizability of results by including different age groups, genders, and ethnicities. Additionally, comprehensive evaluation of quercetin’s effects on specific health conditions, dosage optimization, long-term safety profile, and mechanisms of action is needed. Investigating the potential effects of quercetin on epigenetic regulation may contribute to the identification of new mechanisms of action and therapeutic targets.
7.2.1 Prioritization of future research for clinical translation
Standardization of dosing and pharmacokinetics: The heterogeneity in dosage, formulation, and treatment duration across studies is the most critical barrier to clinical translation. Future work should establish standardized pharmacokinetic profiles, optimal therapeutic windows, and dose–response relationships in humans.
Optimization of bioavailability-enhanced formulations: Despite promising nanocarrier and liposomal approaches, comparative studies are still limited. Prioritizing head-to-head evaluations of nanoformulations (e.g., lipid-based, polymeric, or hybrid systems) under uniform conditions will clarify which strategies most effectively enhance absorption and hepatic delivery.
Large-scale randomized controlled trials (RCTs): Translational progress is hindered by the lack of multicenter RCTs. Future research should prioritize well-designed clinical trials evaluating efficacy, safety, and long-term outcomes in populations with MASLD, alcoholic liver disease, and drug-induced hepatotoxicity.
Mechanistic biomarker discovery: Identification of reliable biomarkers (e.g., Nrf2 activation, HO-1 expression, or mitochondrial markers) is crucial to monitor quercetin’s in vivo activity and therapeutic response. This will enable the integration of molecular signatures into clinical endpoints.
Drug–nutrient and drug–drug interaction studies: Given quercetin’s modulation of cytochrome P450 enzymes and P-glycoprotein, systematic pharmacokinetic interaction studies should be prioritized to ensure safety, particularly in polypharmacy or chronic disease populations.
Personalized medicine approaches: Investigating genetic polymorphisms affecting quercetin metabolism will help identify responders and nonresponders, paving the way for precision supplementation strategies.
Long-term safety and toxicological evaluation: While short-term use appears safe, chronic high-dose exposure requires long-term toxicological assessments, including renal and metabolic effects, to inform regulatory approval.
In conclusion, although the pathophysiological mechanisms underlying quercetin’s hepatoprotective effects have not yet been fully elucidated, current data suggest that this flavonoid may protect liver tissue by reducing oxidative stress, preventing hepatocyte apoptosis, suppressing the inflammatory response, and inhibiting the production of ROS. The use of high doses of quercetin supplements or its use in conjunction with medications requires careful consideration due to potential side effects and toxicity risks. Therefore, the safe and effective administration of quercetin depends on the establishment of ethical and regulatory frameworks that evolve in line with scientific advancements. Recent advances in nanotechnology and targeted delivery systems have enhanced quercetin’s potential to overcome bioavailability barriers, enabling the development of new strategies for disease prevention and treatment. However, these advances also bring with them ethical and regulatory responsibilities in areas such as dose standardization, pharmacokinetic validation, and long-term safety. By overcoming these limitations, quercetin has the potential to be used as an effective therapeutic agent in a wide range of diseases, from liver fibrosis to chronic inflammatory disorders.
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Written By
Mehmet Ali Temiz and Emine Okumus
Submitted: 01 December 2025Reviewed: 10 December 2025Published: 05 May 2026
Open access peer-reviewed chapter
