https://orcid.org/0000-0002-6918-2442
Figures
Abstract
Objective
Age-related hearing loss (ARHL), the most prevalent sensory impairment in older adults, is closely associated with NOD-like receptor thermal protein domain-containing protein 3 (NLRP3) inflammasome activation and mitochondrial dysfunction. Quercetin, a natural flavonoid, shows anti-inflammatory and antioxidant properties, but its role in ARHL remains unclear. In this study, we investigated the protective effects and underlying mechanisms of quercetin on ARHL in a mouse model, focusing on both NLRP3 inflammasome and mitophagy.
Materials and methods
Quercetin was administered intragastrically to C57BL/6J mice from the age of 6 months to 12 months. The function of the hearing system was evaluated by auditory brainstem response (ABR) and hematoxylin and eosin (HE) staining of the cochlea. The levels of oxidative stress markers were detected using specific kits. Gene expression was detected by quantitative reverse transcripation polymerase chain reaction (qRT-PCR) and Western blot.
Results
The results showed that quercetin effectively reduced the ABR threshold shift at 8, 16, and 32 kHz frequencies and improved cochlear tissue morphology. It also reduced oxidative stress and inflammatory factors such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-18 (IL-18), and interleukin-1β (IL-1β), in the cochlea and auditory cortex of C57BL/6J mice. Notably, the activation of the NLRP3 inflammasome was attenuated in the quercetin-treated group, as evidenced by decreased expression of NLRP3, apoptosis-associated speck-like protein (ASC), IL-1β, IL-18, caspase-1 and cleaved caspase-1. Additionally, quercetin treatment promoted the expression of autophagy-related genes in the cochlea and auditory cortex, such as PTEN induced putative kinase 1 (PINK1), Parkinson disease-related protein 2 (PARKIN), BCL2 interacting protein 3 (BNIP3) and microtubule-associated protein 1 light chain 3B (LC3B), and increased the LC3B-II/LC3B-I ratio.
Citation: Feng M, Zhou X, Yang T, Chen Z, Yang G, Jiang X, et al. (2026) Quercetin prevents age-related hearing loss in C57BL/6J mice by activating mitophagy and inhibiting the NLRP3 inflammasome. PLoS One 21(3): e0342423. https://doi.org/10.1371/journal.pone.0342423
Editor: Kota V. Ramana, Noorda College of Osteopathic Medicine, UNITED STATES OF AMERICA
Received: August 30, 2025; Accepted: January 21, 2026; Published: March 9, 2026
Copyright: © 2026 Feng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: National Natural Science Foundation of China (No. 81873702, No. 82571321), National Clinical Research Center for Otolaryngologic Diseases, Beijing, China (code:2024KF008), Natural Science Foundation of Chongqing (2025NSCQ-MSX5224), Chongqing Technology Innovation and Application Development Special Project (No. CSTB2023TIAD-KPX0059) and Major Programs of Chongqing Science and Health Union (No. 2022DBXM006). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
1. Introduction
Age-related hearing loss (ARHL), commonly called presbycusis, is a widespread sensory disorder among the elderly and is characterized by a gradual and progressive loss of sensorineural hearing [1]. According to statistics, more than 40% of individuals aged 65 and over are affected by ARHL [2]. ARHL can result in various complications such as social isolation, depression and dementia, which has a significant impact on overall quality of life in the elderly [3]. Unfortunately, the exact pathogenesis of ARHL is not fully understood, and treatments for ARHL are largely confined to cochlear implants and hearing aids [4]. Therefore, it is critical to explore effective drugs for preventing the onset and progression of ARHL.
During aging, there is a constant, non-infectious, mild inflammation, which contributes to the progression of illnesses associated with aging [5]. Evidence suggests that chronic and low-grade inflammation of cochlear tissue is closely related to ARHL [6], among which the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a key role [7]. The NLRP3 inflammasome is a multiprotein complex that consists of NLRP3, apoptosis-associated speck-like protein (ASC), and Caspase-1. It primarily facilitates the inflammatory responses by triggering the release of inflammatory factors such as interleukin-1β (IL-1β) and interleukin-18 (IL-18) [8], which subsequently lead to cochlear tissue damage and contribute to ARHL.
Recent investigations suggest that mitophagy is crucial for maintaining mitochondrial homeostasis and reducing damage to aging cochlear cells, and age-related decrease in mitophagy may contribute to the onset of ARHL [9]. Activation of mitophagy has been shown to protect cochlear cells potentially by alleviating mitochondrial dysfunction and reducing oxidative stress [10]. Furthermore, mitophagy is also one of the key mechanisms involved in regulating the activation of the NLRP3 inflammasome. It inhibits NLRP3 inflammasome activation by clearing damaged mitochondria and reducing reactive oxygen species (ROS) [11], thereby suppressing the inflammatory cascade and cell death. Given the high energy metabolism demands of cochlear cells and their vulnerability to mitochondrial damage [12], mitophagy has become a crucial pathway for eliminating damaged mitochondria and promoting cellular repair. Consequently, targeting mitophagy along with the NLRP3 inflammasome offers a promising strategy for the prevention and treatment of ARHL.
Quercetin, a common polyphenolic compound, is abundantly found in many fruits and vegetables. It has been shown to have multiple health benefits, including anti-inflammatory, antioxidant, and neuroprotective effects [13], and its functions of promoting mitophagy and inhibiting the activation of the inflammasome play an important role in these effects [14,15]. Previous studies have demonstrated that the intake of quercetin has protective effects against a variety of age-related diseases [16]. However, the potential positive impact of quercetin on ARHL and the mechanisms behind its role in ARHL are yet to be investigated. In this study, we investigated the effects of quercetin in ameliorating ARHL in mice and its underlying mechanisms.
2. Materials and methods
2.1. Animals
C57BL/6J mice (5 months old) weighing 28−29 g were supplied by Chongqing Medical University's Experimental Animal Center (Chongqing, China). All procedures involving animal use and care were approved by the Chongqing University Animal Welfare and Ethics Committee (CQU-IACUC-RE-202508–007). A room with a temperature range of 22–25°C, humidity between 60 and 70%, and a 12-hour alternating light and dark cycle was used for housing the mice. After a month of acclimatization, the mice were randomly assigned into three groups: the control group (6 M), negative control (12 M-vehicle) and quercetin group (12 M-quercetin). Mice in negative control and quercetin group were respectively treated with saline and quercetin (95% purity; CAS No. 117-39-5; purchased from Nanjing Ze Lang Biological Technology Co., Ltd) at a dose of 50 mg/kg/day from 6 to 12 months of age. This dosage was chosen based on a prior study [17]. Throughout the experiment, body weight was measured every month.
2.2. Auditory brainstem responses (ABR) test
The mice underwent anesthesia with 2% isoflurane for induction and 1.5% isoflurane for maintenance prior to each test. Anesthetized mice were kept on a heating pad to ensure their body temperature remained at 37–38°C. Tests were conducted inside a soundproof room, with pure tone bursts at 8, 16, and 32 kHz were delivered to the ear canals of the mice to evoke ABR. Intelligent Hearing Systems (Miami, FL, USA) were used to record ABR from the scalp of the mice. The intensity of the stimulus was measured at 5 dB intervals, beginning from the maximum stimulus intensity and decreasing until waves were no longer visible. ABR thresholds were identified as the minimum stimulus levels where discernible wave peaks appeared in the evoked trace.
2.3. Tissue preparation
The mice were euthanized by cervical dislocation under 5% isoflurane anesthesia. Bilateral temporal bones and brain were rapidly placed in pre-chilled sterile saline. The auditory cortex was dissected from the brain, and bilateral cochleae were removed from the temporal bones.
2.4. Hematoxylin and Eosin (HE) Staining
After fixation in 4% paraformaldehyde for 24 h, cochleae were decalcified in 10% EDTA for 7 days. Tissues were dehydrated through a graded ethanol series, cleared in xylol, and embedded in paraffin. Serial 5-μm sections were cut with a rotary microtome, mounted on glass slides, and stained with HE. ImageJ software was used for all quantitative analyses of tissue staining.
2.5. Assessment of oxidative stress
Levels of malondialdehyde (MDA) and glutathione (GSH), and superoxide dismutase (SOD) activity in the auditory cortex and cochlea were quantified using commercial kits (Nanjing Jiancheng, China) following the manufacturer’s instructions.
2.6. Quantitative reverse transcripation polymerase chain reaction (qRT-PCR)
Total RNA was extracted from mouse cochlea using Trizol Reagent (Thermo Fisher Scientific, USA) in accordance with the manufacturer's instructions. RNA quality was evaluated by determining the A260/A280 ratios using a NanoDrop® ND-1000 spectrophotometer. Complementary DNA synthesis was conducted via reverse transcription using the PrimeScript™ RT Master Mix (Takara, China), following the protocol provided by the manufacturer. Quantitative PCR was carried out with the TB Green® Premix Ex Taq™ II (Takara, China) on a LightCycler 480 system. The primer sequences employed in the experiments are detailed in S1 Table.
2.7. Western blot analysis
Total protein extraction was performed using RIPA buffer supplemented with 1% PMSF and 1% phosphatase inhibitors. The protein concentration was subsequently determined utilizing a BCA protein assay kit (Beyotime, China). Proteins were resolved by SDS-PAGE and subsequently transferred onto PVDF membranes. The membranes were blocked using QuickBlock™ Western blocking buffer for 10 minutes and then incubated overnight with primary antibodies. The primary antibodies employed included PTEN induced putative kinase 1 (PINK1), Parkinson disease-related protein 2 (PARKIN), BCL2 interacting protein 3 (BNIP3), mature IL-1β, mature IL-18 (dilution 1:1000; Abcam, UK), Microtubule-associated protein 1 light chain 3B (LC3B), ASC (dilution 1:1000; Cell Signal Technology, USA), Caspase1, and NLRP3 (dilution 1:3000; Proteintech, China). Subsequently, the membranes were incubated with an appropriate secondary antibody for 1 hour at room temperature. Protein bands were visualized using an ECL detection kit (Epizyme, SQ202L). The western blot results were quantified using ImageJ software.
2.8. Statistical analysis
Statistical analyses were conducted using SPSS software version 27.0. Differences between two groups were assessed using Student's t-test, while differences among three groups were evaluated using one-way analysis of variance (ANOVA). A P-value of less than 0.05 was considered indicative of statistical significance. Data are presented as mean ± standard error of the means (SEM).
3. Result
3.1. Quercetin mitigated ARHL and improved cochlear histomorphology in C57BL/6 mice
Throughout the experiment, all mice exhibited an increase in body weight, but no significant differences were observed between the groups (Fig 1A). The impact of quercetin on preventing ARHL was assessed by measuring changes in auditory thresholds using ABR test. Beginning at 6 months of age, auditory thresholds were evaluated every 3 months until 12 months. Compared to the 12 M-vehicle group, the 12 M-quercetin group demonstrated significantly lower hearing thresholds across all tested frequencies, with the most pronounced reduction observed at 32 kHz at 12 months of age (Figs 1B-1D). HE staining was conducted to assess the effects of quercetin on cochlear histomorphology. The findings indicated undamaged hair cells, spiral ganglion neurons (SGNs), and stria vascularis (SVs) in the 6 M group (Figs 1G, 1J, and 1M). But both Spiral ganglion neurons (SGNs) and hair cells (HCs), especially outer hair cells (OHCs), were severely lost in 12 M-vehicle group (Figs 1E, 1H and 1K). Remarkably, the quercetin treated-mice mice showed less loss of OHCs and SGNs in cochlear histomorphology compared to the 12 M-vehicle group (Figs 1E, 1I and 1L). Additionally, the width of SVs decreased significantly in the 12 M-vehicle group compared to the 6 M group, but was markedly increased in the 12 M-quercetin group compared to the 12 M-vehicle group (Figs 1F, 1N and 1O).
(A) Mean weight change for each group of mice. (B-D) ABR thresholds (8 kHz, 16 kHz, and 32 kHz) in the quercetin treatment group show substantially lower thresholds at 9 and 12 months compared to the control group. (E, F) Quantification of the SGN density and SV thickness. (G-I) Changes in the morphology of the Corti organ. Black arrow: OHCs; Red arrow: IHCs. (J-L) Changes in the morphology of the spiral ganglion. *SGNs. (M-O) Changes in the morphology of SVs. Red arrow: SVs. #p < 0.05, 12 M-quercetin vs 12 M-vehicle; ##p < 0.01, 12 M-quercetin vs 12 M-vehicle; ###p < 0.001, 12 M-quercetin vs 12 M-vehicle; ***p < 0.001, 6 M vs 12 M-quercetin; ns = not statistically significant.
3.2. Quercetin mitigates oxidative stress and inflammation in auditory system
To investigate the impact of quercetin on inflammation in the auditory system, we analyzed changes in inflammatory cytokines using qRT-PCR. The findings revealed a significant upregulation in the mRNA expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-18, and IL-1β in the cochlear and auditory cortex tissues of the 12 M-vehicle group compared to the 6 M group. Conversely, quercetin treatment led to a marked reduction in the mRNA expression levels of these inflammatory cytokines relative to the 12 M-vehicle group (Figs 2A and 2B). The inflammatory response is intricately linked to increased oxidative stress [18]. We further assessed the influence of quercetin on oxidative stress in cochlear and auditory cortex tissues. As illustrated in Figs 2C-2H, the 12 M-vehicle group demonstrated a significant elevation in oxidative stress compared to the 6 M group in both cochlear and auditory cortex tissues. Specifically, the content of MDA was significantly increased (Figs 2C and 2F), directly reflecting the aggravation of oxidative tissue damage. Meanwhile, the function of the core antioxidant defense system was impaired, as evidenced by significant decreases in GSH content (Figs 2D and 2G) and SOD activity (Figs 2E and 2H). However, quercetin intervention ameliorated these alterations, effectively restoring MDA content, GSH content, and SOD activity in both tissues to levels close to the 6M group.
(A, B) mRNA expression levels of TNF-α, IL-6, IL-18, and IL-1β in the cochlea (A) and auditory cortex (B). (C, F) Content of MDA in the cochlea (C) and auditory cortex (F). (D, G) Content of GSH in the cochlea (D) and auditory cortex (G). (E, H) Activity of SOD in the cochlea (E) and auditory cortex (H). **p < 0.01, 6 M vs 12 M-quercetin; ***p < 0.001, 6 M vs 12 M-quercetin; #p < 0.05, 12 M-quercetin vs 12 M-vehicle; ##p < 0.01, 12 M-quercetin vs 12 M-vehicle; ###p < 0.001, 12 M-quercetin vs 12 M-vehicle.
3.3. Quercetin attenuates NLRP3 inflammasome activation in the auditory system
We explored the effects of quercetin on NLRP3 inflammasome activation in the auditory system. The qRT-PCR results demonstrated a significant upregulation of mRNA levels for NLRP3, ASC, and caspase-1 in the cochlea and auditory cortex tissues of the 12 M-vehicle group relative to the 6 M group. In contrast, quercetin treatment effectively reduced the expression of these genes (Figs 3A and 3B). Western blot (WB) analysis corroborated these findings, showing increased protein expression levels of ASC, NLRP3, caspase-1, cleaved caspase-1, mature IL-18 and mature IL-1β in the cochlea and auditory cortex of the 12 M-vehicle group, which were partially reversed following quercetin treatment (Figs 3C and 3D). These results suggest that quercetin effectively attenuates NLRP3 inflammasome activation in the auditory system.
(A, B) The mRNA expression levels of NLPR3, ASC and caspase-1 in the cochlea (A) and auditory cortex (B). (C-D) The protein expression levels of NLRP3, caspase-1, cleaved caspase-1, ASC, mature IL-18, and mature IL-1β in the cochlea (C) and auditory cortex (D). ***p < 0.001, 6 M vs 12 M-quercetin; ##p < 0.01, 12 M-quercetin vs 12 M-vehicle; ###p < 0.001, 12 M-quercetin vs 12 M-vehicle.
3.4. Quercetin enhances mitophagy in the auditory system
Subsequently, we comprehensively assessed the impact of quercetin on auditory system mitophagy by analyzing the expression levels of mitophagy-associated genes in cochlear and auditory cortex tissues. Our results showed that, compared with the 6-month group, the mRNA (Figs 4A and 4B) and protein (Figs 4C and 4D) expression of mitophagy-related genes (PINK1, PARKIN, BNIP3, and LC3B) were significantly downregulated in the 12-month group, accompanied by a decreased the LC3B-II/LC3B-I ratio (Figs 4E and 4F). Notably, this decrease was effectively rescued by quercetin treatment, which significantly upregulated the expression of these genes and further increased the LC3-II/LC3B-I ratio. Collectively, these findings indicate that quercetin promotes mitophagy in the auditory system.
(A, B) The mRNA expression levels of PINK1, PARKIN, BNIP3, and LC3B (A) and auditory cortex (B). (C-D) The protein expression levels of PINK1, PARKIN, BNIP3, and LC3B-I/II in the cochlea (C), and auditory cortex (D). (E) Ratio of LC3B-II/LC3B-I in the cochlea. (F) Ratio of LC3B-II/LC3B-I in the auditory cortex. **p < 0.01, 6 M vs 12 M-quercetin; ***p < 0.001, 6 M vs 12 M-quercetin; ##p < 0.01, 12 M-quercetin vs 12 M-vehicle; ###p < 0.001, 12 M-quercetin vs 12 M-vehicle.
4. Discussion
As the elderly population grows quickly, ARHL is becoming more prevalent in the older population, seriously affecting the quality of life of the elderly [3]. A growing number of studies have shown that inflammation triggered by the NLRP3 inflammasome and decreases in mitophagy were strongly associated with ARHL [8,9]. Furthermore, the activation of the NLRP3 inflammasome has also been confirmed to be associated with mitophagy [19]. A lack or inhibition of mitophagy boosts NLRP3 inflammasome activity and the release of IL-1β and interleukin-1 (IL-1) [20]. Therefore, targeting the regulation of the NLRP3 inflammasome activity and the mitophagy process represents a potential therapeutic strategy for ARHL. In this study, we explored the protective role of quercetin on ARHL in a mouse model, with an emphasis on its influence on the NLRP3 inflammasome and mitophagy.
Flavonoids, plant phenolic compounds with strong antioxidant and anti-inflammatory properties, act as free radical scavengers [21]. Quercetin is a type of flavonoid that is commonly present in fruits and vegetables, with diverse biological activities and potential health benefits [13]. In the guinea pig model, the supplementation of quercetin has been proven to reduce the loss of hair cells induced by noise exposure, and significantly alleviate noise induced hearing loss [22]. And, its protective effect on the function of outer hair cells in the cochleae of rats is also particularly significant [23]. The present study found that the hearing thresholds of C57BL/6J mice gradually increased with age at all frequencies, and exhibited the typical characteristics of ARHL. In contrast, the degree of hearing loss markedly reduced in quercetin-treated mice, compared with the negative control group. It also has been discovered that quercetin can increase the antioxidant activity in the lateral line hair cells of zebrafish, thereby counteracting the damage to the hair cells caused by neomycin [22]. Similar to our findings, the quercetin-treated group also significantly ameliorated the age-related loss of cochlear hair cells and spiral ganglion neurons, as well as the atrophy of the stria vascularis in C57BL/6J mice, and suppressed their oxidative stress levels. These results further demonstrate the potential therapeutic efficacy of quercetin in the treatment of ARHL.
The NLRP3 inflammasome, as a key component of the innate immune response, plays a critical role in the pathological processes of various types of hearing loss [24]. Accumulating evidence indicates that activation of the NLRP3 inflammasome promotes the death of auditory cells in the cochlea and the release of inflammatory cytokines (e.g., IL-1β, IL-18, and TNF-α), thereby contributing to hearing loss induced by drug or noise exposure [25–27]. In contrast, inhibitors targeting the NLRP3 inflammasome have been demonstrated to effectively suppress the release of inflammatory cytokines from cochlear cells, reduce the loss of cochlear auditory cells, and further ameliorate impaired auditory function [28,29]. Similarly, in our study, we identified the activation of the NLRP3 inflammasome and an elevation in inflammatory mediators, including IL-1β, IL-6, IL-18, and TNF-α, within the auditory system of aged C57BL/6 mice. Treatment with quercetin resulted in a significant suppression of NLRP3 inflammasome activation and the associated inflammatory response. These findings further indicate that the NLRP3 inflammasome may serve as a critical target for quercetin in mitigating ARHL.
Autophagy, particularly mitophagy, is essential for the survival of auditory cells, and its dysfunction contributes to hearing loss [30]. Mitophagy, which is primarily initiated via the PINK1/PARKIN pathway or BNIP3 receptors, functions to clear damaged mitochondria [31]. Studies have shown that defective mitophagy leads to mitochondrial damage and accumulation of ROS, thereby activating the NLRP3 inflammasome and contributing to the pathogenesis of various diseases, such as non-alcoholic steatohepatitis and diabetic neuropathy [32,33]. Notably, quercetin has been shown to enhance mitophagy and reduce mitochondrial ROS accumulation, thereby suppressing the activation of the NLRP3 inflammasome [34]. Furthermore, it can inhibit NLRP3 inflammasome activation via targeting heat shock protein 90 or blocking the intracellular translocation of thioredoxin-interacting protein [35]. In our study, the reduced expression of LC3B, PINK1, PARKIN, and BNIP3 proteins in the aging auditory system was observed alongside the activation of the NLRP3 inflammasome. Following quercetin treatment, there was a significant increase in the expression levels of these proteins in the auditory system of mice. These findings further suggest that quercetin activates mitophagy and reduces the expression of NLRP3-regulated inflammation-related proteins, which may be critical mechanisms underlying its protective effects on hearing.
This study has several limitations. First, the relatively low oral bioavailability of quercetin may hinder its direct clinical translation, necessitating the exploration of optimized dose and dosing regimen in future studies. Second, while the results indicate an association between quercetin treatment and the activation of mitophagy as well as inhibition of the NLRP3 inflammasome, causal evidence from loss-of-function experiments is lacking. Future studies employing mitophagy inhibitors, PINK1/Parkin knockout, or NLRP3 knockout models are planned to validate causality. Finally, caution is warranted when extrapolating the findings to humans due to species differences in aging processes, auditory physiology, and drug metabolism between C57BL/6J mice and humans.
5. Conclusion
In summary, this study demonstrated that quercetin effectively mitigated ARHL in mice. Its protective effect is achieved through the enhancement of mitophagy and concurrent inhibition of the NLRP3 inflammasome, which collectively reduce oxidative stress and inflammatory responses.
Supporting information
S1 Table. Primers used for qRT-PCR in this experiment.
https://doi.org/10.1371/journal.pone.0342423.s001
(DOCX)
Acknowledgments
Generative AI statement
The author(s) declare that no Gen AI was used in the creation of this manuscript.
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