Depression is a common and highly recurrent mental disorder globally, characterized by persistent low mood, anxiety, anhedonia, and cognitive impairments (Burcusa and Iacono, 2007; Malhi and Mann, 2018). According to reports by the World Health Organization (WHO), over 300 million people worldwide suffer from depression. More than 700 000 people die due to suicide every year (World Health Organization, 2020). It is expected that by 2030, depression will become the leading cause of disability worldwide (Chen et al., 2024), placing a significant psychological and economic burden on individuals, families, and society. In recent years, treatment methods for depression have continuously evolved, including pharmacotherapy, psychotherapy, neuromodulation technologies, AI-assisted diagnosis and treatment, and lifestyle interventions (Sampogna et al., 2024). However, pharmacological intervention remains the cornerstone of depression treatment, with most currently used antidepressants exhibiting limitations such as a single mechanism of action, slow onset, and significant side effects (Pannu et al., 2021). Therefore, there is an urgent need to develop safe and effective antidepressants that target multiple pathways and mechanisms.

Quercetin (3,3′,4′,5,7-hydroxyflavone) is a natural flavonoid compound widely found in plants such as apples, onions, broccoli, wine, green tea, and ginkgo (Williamson and Manach, 2005; Mirza et al., 2023). Many studies have shown that quercetin exhibits various biological activities, including antioxidant (Xu et al., 2019), anti-inflammatory (Wu et al., 2024), and anticancer properties (Maleki et al., 2021), and can protect the nervous system (Cardozo et al., 2021; Fideles et al., 2023) as well as improve cognitive function (Ebrahimpour et al., 2020). In recent years, research on quercetin’s antidepressant effects has been gradually increasing. Current studies indicate that quercetin enhances the expression of BDNF in the prefrontal cortex and hippocampus of mice, improving anxiety, depression, and cognitive deficits induced by psychosocial stress (Ugwu et al., 2022). Other studies suggest that quercetin regulates Acetyl-H3K9 and inhibits astrocyte ferroptosis, significantly improving depressive-like behaviors in a perimenopausal depression rat model (Wang et al., 2024c). Furthermore, Ge et al. discovered that quercetin reduces apoptosis in the hippocampus and prefrontal cortex of chronic unpredictable stress (CUS) model mice, upregulates Nrf2 protein expression, and increases the phosphorylation levels of ERK and CREB, improving depressive behaviors in mice, similar to the effects of the antidepressant fluoxetine (Ge et al., 2024).

Despite increasing evidence confirming the effectiveness of quercetin in treating depression (Chen et al., 2022), some controversial results remain in the published studies. To clarify the clinical indications of quercetin for depression, a comprehensive and scientific evaluation of animal experimental studies is crucial. Therefore, we have summarized the existing evidence and, for the first time, conducted a meta-analysis of preclinical studies on quercetin’s antidepressant effects, which may provide important clues for future clinical research.

This systematic review and meta-analysis were conducted in accordance with the PRISMA guidelines (Page et al., 2021) and the Cochrane Collaboration’s principles. To avoid duplication with ongoing systematic reviews, we first searched for similar reviews on the INPLASY website and subsequently registered our study (registration number: INPLASY202530047).

In this meta-analysis, we summarized the evidence from 52 published animal studies, which investigated the effects of quercetin supplementation on antidepressant effects across various behavioral and biochemical parameters. The results indicate that quercetin significantly affected animal behavior measures, including immobility time and swimming time in the FST, total distance traveled, time spent in the central area, and the number of entries into the central area in the OFT, immobility time in the TST, sucrose preference in the SPT, the number of entries into the open arms, time spent in the open arms, and time spent in the closed arms in the EPM, as well as biochemical markers such as GSH, SOD, CAT, MDA, TNF-α, IL-6, IL-1β, BDNF, and CORT. However, no significant effect was found on the number of standing episodes in the OFT.

This study shows that, compared to the control group, quercetin significantly increased sucrose preference in the sucrose preference test, reduced immobility time in the forced swimming test (FST) and tail suspension test (TST), and decreased time spent in the closed arms in the elevated plus maze (EPM). Additionally, quercetin increased total distance traveled and had significant effects on central area time and the number of entries into the open arms in the open field test (OFT) and EPM, showing the great effciency of quercetin for relieving depressive symptoms in animal studies. Depressive behavior test indicators are crucial for assessing the progression and therapeutic response of depression. Typically, the more severe the depression, the longer the immobility time, the shorter the distance traveled, and the less time spent in the central area and open arms, with lower sucrose preference (Tong et al., 2023; Ma et al., 2024). As reported by Anggreini, mice under stress showed a reduction in the time spent in open arms and the number of open-arm entries, indicating reduced exploratory activity, which is characteristic of higher anxiety in mice (Anggreini et al., 2019). Ma et al. found that chronic quercetin supplementation enhanced sucrose preference in mice subjected to chronic unpredictable mild stress, alleviating one of the key factors of depressive behavior—anhedonia (Ma et al., 2021). Furthermore, Samad et al. reported that quercetin can prevent stress-induced anxiety and depressive-like behaviors, as well as improve memory in male mice (Samad et al., 2018). In addition, Anjaneyu Lu et al.'s research on the antidepressant activity of quercetin in diabetic rats showed that quercetin reduced immobility time in a dose-dependent manner, which was similar to the effect of the antipsychotic drug fluoxetine and imipramine (Anjaneyulu et al., 2003). Moreover, the antidepressant and anxiolytic-like effects observed in quercetin-treated animals in our study are consistent with the findings of Sameha Merzoug, who reported that quercetin alleviates doxorubicin-induced anxiety-like behaviors and motor dysfunction in the open field and elevated plus maze tests, except for vertical exploration (i.e., the number of standing episodes) (Merzoug et al., 2014).

This study shows that quercetin significantly increases the levels of GSH, SOD, and CAT in animals, and decreases the levels of MDA, TNF-α, IL-6, and IL-1β. The anti-inflammatory and antioxidant effects of quercetin may be one of the important mechanisms underlying its antidepressant effects. Many studies suggest that the anti-inflammatory effects of quercetin may help alleviate neuropsychiatric symptoms. Sah et al. demonstrated that quercetin significantly reduced the levels of IL-1β and IL-6 in rats treated with lipopolysaccharide (LPS), thereby improving anxiety-like symptoms (Sah et al., 2011). These results were also verified in mice subjected to chronic unpredictable stress (CUS) (Mehta et al., 2017; Du et al., 2024). Due to the presence of both catechol and hydroxyl functional groups in its molecular structure, quercetin can directly exert antioxidant effects (Qi et al., 2022). Previously, Şahin et al. showed that quercetin, when administered via intraperitoneal injection, increased the SOD activity in the striatum of rats in the CUMS model (Ahin et al., 2020). One study found that quercetin had a significant effect on the perimenopausal depression rat model, as quercetin treatment significantly increased GSH levels in the brain and reduced the level of the oxidative stress marker MDA (Hou et al., 2025). Another study showed that quercetin alleviated oxidative stress and inflammation in rats by upregulating antioxidant mechanisms and downregulating the expression of COX2 and NF-κB (Bahar et al., 2017).

This study demonstrates that quercetin significantly increases BDNF levels and decreases CORT levels in animals, further supporting the biological basis of its antidepressant action. BDNF is a protein abundantly present in the human brain, which plays a critical role in protecting dendrites and axons, promoting synaptic plasticity, and regulating neuronal survival and intracellular signaling pathways (Kowiański et al., 2018). Clinical studies have shown that BDNF levels are significantly reduced in patients diagnosed with major depressive disorder (Kishi et al., 2017; Shi et al., 2020). CORT is an important glucocorticoid that regulates the body’s response to various stressors, such as psychological and physiological stress. A large body of evidence indicates that patients with depression or those who are chronically stressed typically exhibit overactivation of the hypothalamic-pituitary-adrenal (HPA) axis and elevated cortisol levels (Cubała and Landowski, 2014; Fischer et al., 2017; Druzhkova et al., 2022). Furthermore, existing studies have demonstrated that quercetin and its derivatives may exert neuroprotective effects by interacting with NMDA receptors, thereby reducing neuronal hyperexcitability and damage (Subramanian et al., 2023). Additionally, the modulation of NMDA receptors by quercetin could help restore neurotransmitter balance and ameliorate depressive-like behaviors (Wang et al., 2024c).

The findings of this study may provide multifaceted reference information for the future design of clinical trials of quercetin, which could facilitate the development of quercetin as a potential antidepressant and offer more therapeutic options for patients with depression. First, regarding the selection of subjects, the animal models included in this study cover a variety of methods for inducing depression, suggesting that future clinical trials may consider including patient groups with different etiologies or clinical manifestations of depression to more comprehensively evaluate the efficacy of quercetin. Second, in terms of dosing regimen design, this study has a wide range of quercetin doses and diverse routes of administration. Future clinical trials can refer to this information and, in combination with human pharmacokinetic characteristics, design rational human dosing regimens and routes of administration. Finally, regarding the evaluation of efficacy, this study involves multiple behavioral tests and biochemical indicators as outcome measures. Future clinical trials can draw on these indicators and, in combination with clinical practice, select more sensitive and specific assessment tools to measure the symptom improvement of patients with depression.

To our knowledge, the strength of this study lies in its being the first systematic review and meta-analysis of quercetin’s antidepressant effects in preclinical research. Through a comprehensive analysis of multiple behavioral tests and biochemical indicators, the ameliorative effects of quercetin on depressive-like symptoms in animal experiments were evaluated. Our findings provide practical value for translating animal data to clinical evidence.

However, there are several limitations in our systematic review and meta-analysis. First, the number of studies included is limited, and the total sample size is relatively small. Second, the included studies lacked standardized protocols regarding animal species, depression modeling methods, treatment interventions, and outcome assessment methods, which led to higher heterogeneity. Third, most of the studies included did not implement effective allocation concealment measures, nor did they blind the researchers or outcome assessors, which may have introduced selection, performance, and detection biases. Finally, although the sensitivity analysis indicated that the results were relatively stable, the significant risk of bias remains a concern. Therefore, further high-quality studies are urgently needed to validate the results presented in this study.

Subgroup analyses revealed that the effects of quercetin on the total distance traveled in the open field test were significantly influenced by dose, treatment duration, and animal species. Specifically, high doses (≥60 mg/kg) and prolonged treatment durations (2–4 weeks) significantly increased the total distance traveled in rats. However, no significant effects were observed in mice or under conditions of low doses and short treatment durations. Collectively, these findings indicate that treatment duration, dosage, and animal species significantly influence the therapeutic efficacy of quercetin. Therefore, future studies should further standardize experimental protocols.

In this study, we conducted a Meta-analysis for the first time to demonstrate that quercetin exhibits significant antidepressant effects in animal studies. The underlying mechanisms may involve the regulation of oxidative stress, inflammatory responses, neurotrophic factors, and HPA axis function. Although the results are limited by the heterogeneity of animal models and the risk of bias, the multitarget properties of quercetin provide a theoretical basis for its potential as an antidepressant agent. Future research should focus on standardized preclinical studies and explore its clinical translation, including dose optimization, sex differences, and combination therapy strategies.