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. 2025 Sep 9. Online ahead of print. doi: 10.1039/d5md00426h

Polyphenolic compounds as protective agents against cisplatin-induced ototoxicity with molecular mechanisms and clinical potential

Tong Wei a,b, Jing Nie b, Dongbo Wang b, Huina Wu b, Lijiao Guan b, Jiyong Wu a,b,✉
PMCID: PMC12423776  PMID: 40951767

Abstract

Cisplatin remains a cornerstone in the treatment of various solid tumors due to its exceptional antineoplastic efficacy. However, its clinical utility is significantly constrained by severe adverse effects, with ototoxicity emerging as particularly problematic due to its potential to cause permanent hearing impairment and substantially diminish patient quality of life. Recent investigations into mitigating cisplatin-induced ototoxicity have identified natural polyphenolic compounds as promising protective agents, attributable to their diverse biological activities and potent antioxidant properties. This review critically examines the molecular mechanisms underlying cisplatin-induced cochlear damage and systematically evaluates recent advances in employing polyphenolic compounds as otoprotective interventions. Evidence indicates these bioactive molecules attenuate cisplatin-mediated hearing loss through multiple complementary pathways, including modulation of oxidative stress, inflammatory responses, and apoptotic cascades within the cochlear architecture. However, significant challenges, such as low bioavailability and potential interference with cisplatin's antitumor efficacy, hinder their clinical translation. Based on evidence from studies published between 2010 and 2025, with a focus on advances from the last five years, this review systematically outlines protective mechanisms while critically addressing current research limitations. It further proposes future directions, highlighting advanced drug delivery systems and innovative therapeutic strategies. These insights provide a robust mechanistic framework for the rational design and development of novel otoprotective strategies that preserve cisplatin's antitumor efficacy while minimizing its ototoxic potential.

Graphical abstract merges cisplatin ototoxicity pathways, polyphenol protection, chemo-synergy conflicts, and translational roadmap from preclinical to therapy.graphic file with name d5md00426h-ga.jpg

1. Introduction

Cisplatin, a first-line chemotherapeutic agent for solid malignancies including ovarian, cervical, lung, prostate, nasopharyngeal, and breast cancers, demonstrates dose-limiting therapeutic efficacy due to severe off-target toxicities, among which ototoxicity remains a particularly serious complication. Mechanistically, cisplatin-induced ototoxicity arises from a pathophysiological cascade involving disruption of cochlear microarchitecture—characterized by apoptosis of sensory hair cells and degeneration of spiral ganglion neurons—coupled with oxidative stress-mediated breakdown of cochlear homeostasis. This ototoxic injury culminates in irreversible sensorineural hearing loss (SNHL), typically manifesting as bilateral, progressive audiometric decline. Beyond its direct auditory consequences, cisplatin-induced SNHL imposes profound multisystemic repercussions: pediatric patients experience impaired language acquisition trajectories, while adolescents and adults face increased risks of social isolation, accelerated cognitive decline, and occupational restrictions—collectively diminishing lifelong functional outcomes.1,2

Natural polyphenolic compounds, a class of plant-derived secondary metabolites, demonstrate significant potential in mitigating cisplatin-induced ototoxicity through their redox-modulating, anti-inflammatory, and cell death-regulating capacities.3 Cumulative research has shown that such compounds can effectively ameliorate cisplatin-induced cochlear cell damage through mechanisms involving efficient neutralization of free radicals, potentiation of endogenous antioxidant enzyme cascades, inhibition of ferroptosis pathway, and modulation of apoptosis-related signaling pathways. The remarkable structural diversity—encompassing 8000+ known derivatives—provides a robust molecular repertoire for developing novel otoprotective agents. Notably, several principal subclasses, including lignans (e.g., silymarin), flavonoids (e.g., quercetin), phenolic acids (e.g., ferulic acid), and stilbenes (e.g., resveratrol), exhibit distinct pharmacophores that enable targeted modulation of oxidative stress, inflammation, and apoptosis pathways implicated in auditory dysfunction.4 This review aims to systematically elucidate the molecular pathogenesis underlying cisplatin ototoxicity and investigate structure-guided intervention strategies based on the functional classification of polyphenolic phytochemicals. Focusing on mechanistic insights, we analyze the signaling networks through which these compounds exert protective effects by regulating oxidative stress status, inflammatory responses, and cell death pathways, ultimately aiming to provide a theoretical foundation for clinical translation.

2. Cisplatin ototoxicity

2.1. Mechanism of cisplatin ototoxicity

Cisplatin-induced ototoxicity, clinically characterized by high-frequency hearing loss, has emerged as a prominent focus in current research. This pathological manifestation is closely associated with cisplatin's toxic effects within the inner ear.2 Studies have established that cisplatin-induced ototoxicity is mediated through multiple interconnected mechanisms: excessive generation of reactive oxygen species (ROS), sustained activation of inflammatory cascades, dysregulated cellular uptake of cisplatin, and impaired autophagic flux.5 Collectively, these pathogenic processes drive progressive cellular injury in the inner ear microenvironment, ultimately resulting in irreversible sensorineural hearing loss.6

Cisplatin is capable of directly penetrating cochlear outer hair cells (OHCs), inducing irreversible cytostructural damage and ultrastructural disintegration.5 Furthermore, through targeting cellular junction proteins, cisplatin provokes vascular stripe injury, consequently disrupting endolymphatic electrolyte homeostasis and generating abnormal cochlear membrane bioelectrical potentials. This injury disrupts cochlear microenvironmental stability by facilitating cisplatin penetration into the endolymphatic compartments, promoting passive release of cellular disintegration products from cochlear cells, and exacerbating inner ear cell damage. The ensuing inflammatory responses involves a self-perpetuating cycle where ROS and inflammatory mediators form a pathogenic positive feedback loop, significantly amplifying oxidative stress-mediated cell damage. Additionally, mitophagy—an evolutionarily conserved selective autophagy process—has been implicated in cisplatin-induced ototoxicity. Dynamin-related protein 1 (DRP1), a cytosolic GTPase governing mitochondrial fission dynamics, maintains mitochondrial functional integrity, and structural homeostasis. Conversely, the small non-coding RNA miR-34a-mediated suppression of DRP1 expression disrupts mitophagic flux, ultimately precipitating cochlear damage.7 Furthermore, the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway exerts pleiotropic effects on in cochlear cellular processes encompassing apoptotic regulation, and proliferative control. Pharmacological targeting of epigenetic modifiers reveals therapeutic potential: inhibition of lysine-specific demethylase 5A (KDM5A) activates PI3K/AKT signaling, which restores mitochondrial homeostasis, reduces ROS overaccumulation, and enhances OHCs resistance to cisplatin.8 Similarly, inhibition of protein arginine methyltransferase 6 (PRMT6)—an epigenetic regulator functionally analogous to KDM5A—confers cytoprotection to cochlear hair cells through ROS suppression and blockade of mitochondrion apoptotic pathways.9,10 The cochlear immune microenvironment further modulates cisplatin toxicity, with tissue-resident macrophages executing dual regulatory roles through initiation of pro-inflammatory signaling cascades and coordination of tissue-reparative mechanisms post-injury. Experimental evidence demonstrates that partial macrophage depletion mitigates cisplatin-associated ototoxic pathology.11 Pharmacological interventions using α-lipoic acid and grape seed extract demonstrate substantial neuroprotective effects on spiral ganglion neuron apoptosis through two synergistic mechanisms: efficient neutralization of cytotoxic ROS and enhanced activation of endogenous antioxidant enzymatic systems in cochlear cellular populations. Collectively, these mechanisms mitigate cisplatin-mediated ototoxic damage.12

The pathomechanism of cisplatin ototoxicity manifests as a multifaceted cascade involving multiple molecular targets. The primary mechanisms include the accumulation of cisplatin in cochlear OHCs, where mitochondrial dysfunction driven by excessive ROS production triggers oxidative stress, ultimately leading to DNA damage and lipid peroxidation. In addition, nitrative stress, which synergizes with cisplatin-induced oxidative damage through multiple pathways (protein nitration, mitochondrial dysfunction, ferroptosis, etc.), represents one of the core mechanisms underlying cochlear hair cell death and hearing loss. Nitrative stress often collaborates with oxidative stress in contributing to cochlear synaptic dysfunction. Cisplatin increases the production of ROS and reactive nitrogen species (RNS), leading to a decrease in mitochondrial membrane potential (MMP) and glycolytic metabolism disorders in cochlear hair cells, ultimately triggering cell apoptosis.13,14 For example, SIRT3 deficiency exacerbates ROS accumulation and nitrative stress, while SIRT3 overexpression exerts a protective effect. The second involves the initiation of inflammatory cascades, whereby ROS activate NOD-like receptor thermal protein domain associated protein 3 (NLRP3)inflammasome complexes, stimulate the production of pro-inflammatory factors, and establish positive feedback loops with immunological responses mediated by macrophages, aggravating vascular striae and spiral ganglion damage. Ultimately, several pathways trigger programmed cell death: cisplatin induces irreversible cochlear cell apoptosis by activating caspase-3 apoptotic pathways and inhibiting DRP-1-dependent mitochondrial autophagy via miR-34a, while simultaneously disrupting epigenetic regulators such as KDM5A and PRMT6. Through the PI3K/AKT signaling axis, these changes worsen ROS buildup and mitochondrial metabolic diseases. Given the intricacy of cisplatin ototoxicity pathways, developing new preventative measures remains vital.

2.2. Current status of cisplatin ototoxicity treatment

To mitigate the ototoxicity of cisplatin, researchers have explored numerous protective strategies. Various interventions documented in the literature include antioxidants, anti-inflammatory drugs, transporter protein inhibitors, cellular pathway inhibitors, and combination drug regimens.15 However, only sodium thiosulfate has been clinically approved for use, and its specific mechanism is to directly bind cisplatin to form a nontoxic complex while elevating glutathione levels to enhance antioxidant capacity; two phase III trials (SIOPEL6, COG ACCL0431) showed a 50% reduction in the incidence of ototoxicity However, its broad-spectrum antioxidant properties may affect the anticancer activity of cisplatin, which highlights the need to develop specific targeted therapies.16–21 In addition, Ebselen, a synthetic analog of the antioxidant enzyme GPx1 with anti-inflammatory properties, has also shown beneficial effects against cisplatin ototoxicity, and its oral formulation, SPI-1005, is undergoing clinical trials.22 Nevertheless, most antioxidants have been limited by concerns that they might compromise cisplatin's antitumor efficacy, as the drug's anticancer properties primarily stem from its ability to form DNA adducts and generate ROS in cancer cells. This paradox remains a central challenge in the development of otoprotective agents.23

3. Research on using natural polyphenolic substances to reduce the ototoxicity of cisplatin

Contemporary research has significantly advanced our understanding of natural polyphenolic compounds—a prominent class of plant-derived secondary metabolites—by elucidating critical structure–activity relationships within their diverse chemical architectures, encompassing subclasses like flavonoids, phenolic acids, lignans, stilbenes and their multifaceted biological activities.24,25 These compounds exhibit multi-target mechanisms, including antioxidant, anti-inflammatory, and cytoprotective effects, potentially alleviating cisplatin-induced ototoxicity via distinct molecular pathways.26

3.1. Flavonoids

As fundamental bioactive constituents of natural antioxidants, flavonoids exhibit multidimensional antioxidant capabilities through coordinated molecular mechanisms. Their distinctive phenolic hydroxyl moieties effectively terminate lipid peroxidation cascades by directly neutralizing ROS via hydrogen atom transfer mechanisms. Beyond this primary scavenging function, these compounds establish comprehensive cellular protection through synergistic interactions: activation of the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2/antioxidant response element (Keap1/Nrf2/ARE) signaling axis to amplify endogenous antioxidant defense systems while selective chelation of redox-active transition metals (Fe2+/Cu2+) inhibits Fenton reaction-driven hydroxyl radical production. The Nrf2/Keap1/ARE signaling pathway has been extensively studied and is recognized as an established mechanism. Additionally, flavonoids precisely regulate nitric oxide homeostasis through dual regulation—suppressing inducible nitric oxide synthase (iNOS) overexpression while directly neutralizing reactive nitrogen species. Moreover, the nitric acid stress pathway plays a more prominent role in ototoxicity, whereas the primary mechanism of action of cisplatin in cancer cells relies on DNA cross-linking and oxidative stress rather than nitric acid stress. Thus, compounds targeting nitric acid stress act only in auditory cells and do not affect the sensitivity of cancer cells to cisplatin. This review concentrates on representative flavonoids.27–30 This review concentrates on representative flavonoids including quercetin, epigallocatechin gallate (EGCG), and curcumin, systematically elucidating their molecular mechanisms and therapeutic efficacy in alleviating cisplatin-related auditory toxicity through targeted regulation of oxidative stress pathways, mitochondrial functional homeostasis, and apoptosis-related signaling transduction networks (Fig. 2).

Fig. 2. Flavonoid monomers in traditional Chinese medicine to alleviate the ototoxicity of cisplatin.

Fig. 2

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3.1.1. Quercetin

Quercetin, a polyphenolic compound within the flavonoid family, demonstrates anti-inflammatory, anti-allergic, antiviral, and antineoplastic pharmacological properties.31 Gundogdu et al. elucidated quercetin's otoprotective efficacy against cisplatin-induced ototoxicity through concerted mechanisms: attenuation of calcium ion dysregulation, chelation of redox-active transition metals (Fe2+/Cu2+), inhibition of xanthine oxidase-mediated superoxide production, and neutralization of ROS-induced oxidative damage (Fig. 1). These mechanistic insights establish a robust foundation for subsequent pathophysiological investigations.32 Lee et al. employed a zebrafish model to investigate quercetin otoprotective potential against cisplatin-induced auditory impairment. Experimental results showed that co-administration with quercetin significantly attenuated cisplatin-related pathological manifestations, including cellular necrotic processes, mitochondrial bioenergetic collapse, apoptosis-mediated hair cell loss, and cochlear ultrastructural damage. These findings mechanistically indicate quercetin's therapeutic ability to mitigate ototoxicity by coordinating several cell death pathways.33 While direct research evidence characterizing the specific pathways of quercetin remain elusive, its cytoprotective effects manifest through multilayered molecular regulation. Quercetin decreases intracellular calcium homeostasis while increasing mitochondrial membrane potential. The compound inhibits the expression of phosphorylated c-Jun N-terminal kinase (p-JNK) and the creation of pro-apoptotic proteins while simultaneously increasing anti-apoptotic proteins and inhibiting cytochrome C release, thereby attenuating apoptotic cascade progression.26 Current evidence establishes that the protective effect of quercetin against cisplatin-induced ototoxicity is primarily attributed to its potent antioxidant properties and regulation of apoptotic pathways. Preclinical investigations further demonstrate quercetin's hepatorenal protective efficacy against cisplatin-associated toxicity.34,35 As a naturally derived bioactive compound, quercetin merits comprehensive exploration for therapeutic translation, particularly in developing adjuvant strategies to counteract chemotherapy-induced multi-organ damage.

Fig. 1. Mechanism of flavonoids compounds to attenuate cisplatin ototoxicity.

Fig. 1

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3.1.2. Epigallocatechin gallate

Epigallocatechin gallate (EGCG), the predominant catechin polyphenol in green tea, has garnered substantial attention due to its multifaceted therapeutic mechanisms in auditory protection. The three principal pathways through which EGCG protects the cochlea involve anti-inflammatory modulation, pro-neural regeneration, and antioxidant protection. Regarding antioxidant defense, EGCG exerts protective effects by targeting ROS neutralization within the cochlear microenvironment. Remarkably, substantial evidence additionally demonstrated that EGCG selectively inhibits ROS-generating pathways during cochlear pathological progression while concurrently suppressing oxidative stress-driven apoptotic cascades.36,37 In elucidating the neural regenerative mechanisms, Zhang et al. demonstrated that EGCG enhances cellular proliferation and neuronal differentiation of cochlear neural stem cells by activating the PI3K/AKT signaling cascade, thereby establishing a novel therapeutic framework for stem cell-based interventions in sensorineural hearing loss.38 Jiang et al. demonstrated that EGCG inhibits STAT1 phosphorylation, effectively suppressing superoxide generation, preserving mitochondrial membrane potential stability, and reducing oxidative cellular damage. This establishes a foundation for novel therapeutic strategies against drug-induced hearing loss.39 Additionally, EGCG contributed to enhance outer hair cell survival in the basal region of the cochlea by 35%, improve auditory brainstem response thresholds, and reduce oxidative stress and apoptotic markers in a cisplatin-induced rat model. Vitro studies revealed that EGCG reduces the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) and STAT1, providing protection by enhancing the ratio of activator of transcription 3 (STAT3)/STAT1.40 Collectively, these findings demonstrate that EGCG provides hearing protection via pleiotropic mechanisms, with STAT1 emerging as a central molecular target (Fig. 1). In addition to its otoprotective properties, EGCG demonstrated concurrent efficacy in mitigating cisplatin-mediated multiorgan toxicity, particularly in the hepatic and renal systems.41,42 However, the inference of this target has not been verified in human ear tissues. Future studies need to clarify this target through more in vivo and in vitro experiments. The multimodal cochlear protective actions of EGCG, particularly its regulatory influence on STAT1 signaling, underscore its significant translational potential in auditory preservation and functional recovery, while offering innovative frameworks for the developing targeted therapeutic interventions.

3.1.3. Curcumin

Curcumin, a natural polyphenol derived from Curcuma longa rhizomes, has evidenced considerable therapeutic potential in oncology studies.43 Experimental evidence substantiates its broad-spectrum antitumor efficacy across multiple biological systems, manifesting significant inhibitory effects on multiple cancer phenotypes.44 The mechanistic foundation of curcumin lies in its dual antioxidant and anti-inflammatory capacities. By modulating thioredoxin reductase activity and specifically suppressing two critical pro-inflammatory signaling hubs, nuclear factor kappa-light-chain-enhancer of activated B cells () and STAT3, curcumin maintains redox balance. The antitumor efficacy of curcumin is attributed to its ability of suppressing pro-oncogenic effectors, including B-cell lymphoma 2 (Bcl-2), cyclooxygenase-2 (COX-2), and cyclin D1 (CCND1). This Synergistic suppression operates through three complementary mechanisms: it arrests the progression of the neoplastic cell cycle, triggers programmed cell death pathway, and inhibits the activation of cancer stem cells. Notably, this synergistic antioxidant and anti-inflammatory properties of curcumin demonstrate therapeutic potential in otoprotection. By attenuating oxidative stress-mediated cochlear damage and inflammatory pathway hyperactivation, curcumin demonstrates robust otoprotective effects against pharmacologically induced cochlear injury.45 Curcumin triggers ferroptosis in tumor cells through upregulation of critical ferroptosis regulators (ACSL4 and TFR1), thereby promoting iron-dependent lipid peroxidation.46 Fetoni et al. also demonstrated that curcumin co-administration with cisplatin effectively reduced chemotherapy-induced systemic toxicity. However, their findings revealed that this phenomenon can be illustrated via bidirectional regulation of the heme oxygenase-1/4-hydroxynonenal (HO-1/4-HNE) signaling pathway. This therapeutic strategy achieved a 42% enhancement in cochlear hair cell survival rates while reducing auditory brainstem response threshold shifts.47 Mechanistically, Curcumin's otoprotective effects are mediated through multifaceted regulatory actions, including activation of the Nrf2/HO-1 pathway, attenuation p53 dephosphorylation, and suppression of NF-κB nuclear translocation.48 However, except for the Nrf2/HO-1 pathway, the research on other mechanisms is too limited, and further verification is still needed in the future. As a prototypical flavonoid, curcumin exemplifies an innovative paradigm for integrated oncotherapy and treatment-related toxicity mitigation.

3.1.4. Other flavonoids

Beyond the compounds previously discussed, additional flavonoid polyphenols demonstrate notable otoprotective efficacy. Notably, puerarin—a bioactive constituent isolated from Pueraria mirifica—exhibits substantial therapeutic potential in mitigating SNHL.49 This compound suppressed caspase-3/Bax-dependent apoptotic signaling through targeted modulation of the transient receptor potential vanilloid 1/inositol 1,4,5-trisphosphate receptor type 1/p65 (TRPV1/IP3R1/p65) signaling axis (Fig. 1), thereby restoring intracellular calcium homeostasis and mitigating ROS overproduction. This coordinated intervention concurrently elevated cochlear hair cell viability rates to 83%.50 Genistein, as the first isoflavonoids isolated from Auricularia auricula, is particularly prominent in ototoxicity interventions due to its multi-targeted anti-inflammatory properties, alongside its role in preventing osteoporosis and reducing cardiovascular disease risk. By constructing a model of cisplatin injury, Tang et al. demonstrated that genistein intervention enhances superoxide dismutase (SOD) activity in cochlear tissue by 1.8-fold and reduces malondialdehyde (MDA) levels by 45%, while inhibiting NF-κB nuclear translocation through modulation of the Nrf2-Keap1 pathway. This action significantly resolves oxidative-inflammatory crosstalk imbalance.51–53 Research by Lu et al. demonstrated that Nobiletin, a characteristic polymethoxy flavonoid derived from citrus peel, attenuates cisplatin-induced ototoxicity primarily through oxidative stress mitigation and apoptotic pathway suppression. Mechanistic investigations further demonstrate its capacity to inhibit autophagic flux and modulate ferroptosis via the Nrf2/glutathione peroxidase 4 (GPX4) signaling axis.54 Collectively, these investigations demonstrate that flavonoids confer synergistic cytoprotection through a dynamically integrated molecular network that encompassing calcium homeostasis maintenance, redox-inflammatory equilibrium regulation, and modulation of programmed cell death pathways. These polypharmacological synergies establish a transformative framework for developing low-toxicity, high-selectivity therapeutics against cisplatin-induced ototoxicity (Fig. 2).

3.2. Phenolic acids

Naturally occurring phenolic acid derivatives demonstrate pleiotropic pharmacological profiles against oxidative stress, conferring cellular protection through redox-modulatory mechanisms. Significantly, ferulic acid, caffeic acid, and gallic acid exhibit robust antioxidant activity, while compounds like tanshinic acid B, tanshinic acid A, rosmarinic acid, and stilbene acid exhibit potent free radical scavenging capacity.55 Phenolic acids containing axially chiral aldehyde moieties, such as gossypol, have demonstrated potential therapeutic efficacy in various diseases, including HIV/AIDS, diabetic complications, and malignancies.56 Phenolic acid compounds, with their antioxidant properties and various biological effects, are valuable targets for further research and potential therapeutic development (Fig. 4).

Fig. 4. Phenolic acid monomers from traditional Chinese medicine to alleviate the ototoxicity of cisplatin.

Fig. 4

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3.2.1. Ferulic acid

Ferulic acid (FA), a phenolic acid predominantly derived from Ranunculaceae and Poaceae families, possesses diverse biological activities including antifungal, antioxidant, tyrosinase inhibitory, anti-inflammatory, antithrombotic, antibacterial, and antitumor properties.57,58 Bao et al. demonstrated that FA exerts its anticancer effects through three interconnected mechanisms: cell cycle arrest at G0/G1 phase, activation of autophagic processes, and inhibition of migration and angiogenesis. Importantly, FA demonstrates synergistic potential in combination therapies by enhancing drug sensitivity and mitigating adverse reactions, like ototoxicity.59–62 Cho et al. investigated FA's protective effects against cisplatin-induced ototoxicity and revealed that FA suppresses ROS formation while enhancing endogenous antioxidant production.63 The antioxidant and otoprotective effects of FA are primarily attributed to its activation of the Nrf2/HO-1 signaling pathway.36 Under normal physiological conditions, Nrf2, a master regulator of the oxidative stress response, binds to Keap1 and is maintained at low levels in the cytoplasm. However, under oxidative stress conditions, Nrf2 dissociates from Keap1, translocate to nucleus, and induces the expression of antioxidant and detoxification enzymes through the ARE (Fig. 3). This process is crucial for reducing oxidative damage, regulating apoptosis pathways, controlling inflammation, and promoting angiogenesis.64,65 Mechanistically, FA confers cytoprotective effects against cisplatin-induced ototoxicity through modulation of autophagy. Experimental studies reveal that FA exhibits dual regulatory roles under cisplatin-induced oxidative stress: initiating the MAPK signaling cascade while simultaneously balancing autophagic flux and apoptotic pathway activity. Although the role of autophagy in cytoprotection has been widely recognized, how FA precisely regulates the balance between autophagic flux and apoptotic pathways remains in the preliminary research stage.65

Fig. 3. Mechanism of phenolic acids compounds to attenuate cisplatin ototoxicity.

Fig. 3

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Significantly, the triggered autophagy exerts cytoprotective effects by promoting intracellular nutrient recycling, thereby enabling cellular adaptation to metabolic stress.66 FA emerges as a potential regulator of the crucial balance between pro-survival autophagy and programmed cell death, attributed to its dual regulatory capacity. This mechanistic insight provides novel pharmacological perspective for developing targeted interventions against cisplatin-associated auditory toxicity, particularly through strategic modulation of the interplay between autophagy and apoptosis.

3.2.2. Caffeic acid

Caffeic acid (CA), a classic derivative of hydroxycinnamic acid, is widely distributed in various food sources, including fermented beverages and botanical products.67 The structural basis for these bioactivities resides in its unique phenylpropanoid framework, where the catechol moiety within the caffeoyl group serves as the redox-active pharmacophore responsible for electron transfer processes.68 Emerging evidence suggests that CA holds therapeutic promise in multiple diseases like diabetes, cancer, Alzheimer's disease (AD), atherosclerosis, and various bacterial or viral diseases.69 Mechanistically, the catechol structure of CA confers potent free radical scavenging activity, enabling effective neutralization ROS and disruption of oxidative stress cascade.70 CA also exhibits anti-inflammatory properties through direct inhibition of gasdermin D activation, thereby preventing the release of pro-inflammatory cytokines.71 The synergistic interplay between its antioxidant and anti-inflammatory mechanisms establishes a crucial pharmacological foundation for mitigating cisplatin-induced toxicity. Corroborating experimental findings confirms CA's protective effects on cochlear auditory function, particularly in limiting noise exposure-induced meso-basal cochlear transcellular apoptosis. This protection is achieved through dual mechanisms: activation of endogenous cytoprotective systems and downregulation of NF-κB/IL-1β expression in cochlear tissues, collectively attenuating cisplatin-associated oxidative damage.72 Further mechanistic validation by Choi et al. demonstrated CA significantly reduce auditory hair cell loss in cisplatin-treated HEI-OC1 models, primarily through ROS scavenging and modulation of the Bcl-2/Bax apoptosis axis.73

3.2.3. Gallic acid

Gallic acid (GA), a prototypical phenolic acid, exhibits significant anti-inflammatory and antioxidant capacities, and demonstrates anticancer efficacy via multi-targeted molecular interactions.74 Its synergistic antioxidant-anti-inflammatory mechanism is composed of three coordinated actions: firstly, it directly inhibits NF-κB nuclear translocation, thereby suppressing downstream pro-inflammatory mediators such as COX-2 and iNOS; secondly, it activates the Nrf2-ARE pathway, enhancing the activities of SOD and GPx; and thirdly, it chelates transition metal ions to block the Fenton reaction.75,76 These coordinated actions collectively underpin the therapeutic potential of GA in modulating oxidative-inflammatory pathologies and highlight its role as a promising candidate for multi-targeted therapeutic strategies. Zhang et al. elucidated GA's concentration- and time-dependently inhibits proliferation of non-small cell lung cancer cells (A549). The underlying mechanism involves dual regulation of apoptotic pathways through two coordinated actions: disrupting the mitochondrial apoptotic threshold by upregulating pro-apoptotic Bax while downregulating anti-apoptotic Bcl-2, combined with suppression of JAK/STAT3 signaling axis phosphorylation, which synergistically enhances cisplatin chemosensitivity.77 Additionally, Gallic acid suppresses the inflammatory cascade by inhibiting key MAPK nodes (ERK1/2, p38, JNK), decreases cochlear MDA levels, and boosts SOD activity, ameliorating cisplatin-induced oxidative damage.78 Experimental investigation by Kilic et al. demonstrated that GA pretreatment attenuated cisplatin-induced auditory brainstem response threshold shifts by 21 dB while significantly enhancing cochlear hair cell survival rates.79 Although the core molecular targets and signaling networks underlying GA-mediated otoprotection still require more in vivo and in vitro experimental validation, an increasing number of research findings suggest that its therapeutic effects may originate from the synergistic action of an oxidative stress-inflammation-apoptosis regulatory triad. This tripartite regulatory axis operates through integrated mechanisms: antioxidant activity via metal chelation and Nrf2 pathway activation, anti-inflammatory effects through NF-κB/MAPK pathway suppression, and apoptotic modulation via Bcl-2/Bax ratio regulation (Fig. 3), collectively establishing a multi-scale biological network spanning molecular to tissue levels.80 As a pleiotropic natural compound exhibiting significant substantial otoprotective potential, future investigations should prioritize mechanistic elucidation of GA's protective pathways to facilitate the translational development of targeted therapeutic strategies (Fig. 4).

3.3. Lignans

Lignans represent a class of naturally occurring polyphenolic compounds that are ubiquitously distributed across plant matrices including roots, stems, leaves, bark, and reproductive organs, predominantly in unconjugated forms.81 Representative bioactive lignans such as silymarin and Honokiol exhibit a broad spectrum of pharmacological properties, including antimicrobial efficacy, antiviral activity, and insulin sensitivity enhancement.82 Current research prioritizes their neuroprotective potential, particularly in therapeutic interventions targeting neurodegenerative pathologies such as AD. Mechanistic investigations reveal lignans preserve neuronal integrity and ameliorate cognitive deficits through tripartite pathways: attenuation of oxidative stress via antioxidant actions, suppression of inflammatory responses through anti-inflammatory mechanisms, and inhibition of apoptosis via modulation of pro-survival signaling pathways.83 This multimodal pharmacological profile positions lignans as promising candidates for counteracting cisplatin-induced ototoxicity through analogous protective mechanisms (Fig. 6).

Fig. 6. Lignans monomers from traditional Chinese medicine to alleviate the ototoxicity of cisplatin.

Fig. 6

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3.3.1. Silymarin

Silymarin, a flavonolignan complex formed through the conjugation of phenylpropanoid derivatives, is primarily isolated from the fruits and seeds of Silybum marianum.84 Functioning as a potent redox modulator, this dietary phytochemical exhibits targeted biodistribution to cochlear and hepatic tissues following oral administration, where it enhances endogenous antioxidant defense systems.85 The otoprotective effects of silymarin against cisplatin toxicity are mediated through two principal mechanisms. Primarily, silymarin disrupts tumor necrosis factor-alpha/tumor necrosis factor receptor 1 (TNF-α/TNFR1) complex formation, thereby suppressing activation cascades of cysteine aspartic acid-specific proteases-8/10 (caspase-8/10) and their downstream effectors caspase-3/7.86 Secondarily, silymarin modulates the Bcl-2 family of proteins, stabilizing mitochondrial membrane potential, reducing cytochrome C release, and simultaneously preventing the formation of apoptosomes and the activation of caspase-9.87 This dual-targeting mechanism orchestrates synergistic blockade of inflammation-apoptosis crosstalk by simultaneously modulating TLR4/TNF-α and Bcl-2/caspase pathways (Fig. 5). The TLR4/TNF-α signaling axis remains underexplored in cisplatin-induced ototoxicity yet holds significant therapeutic potential as a key mediator linking innate immune activation to cochlear inflammatory damage.86 This approach overcomes the limitations of conventional single-target monotherapies and offers innovative therapeutic perspectives for mitigating chemotherapy-induced ototoxicity.

Fig. 5. Mechanism of lignans compounds to attenuate cisplatin ototoxicity.

Fig. 5

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3.3.2. Honokiol

Honokiol, a plant-derived polyphenol, demonstrates dual chemo-sensitizing and organo-protective functions, enabling synergistic enhancement of chemotherapy efficacy while mitigating off-target toxicity.88 Experimental results confirm that and thujaplicin exhibit significant tumour suppressive effects in a cisplatin-induced mouse colon cancer model. It may enhance the therapeutic effect of cisplatin through two complementary mechanisms: up-regulating pro-apoptotic protein expression to enhance tumor cell chemosensitivity and inhibiting the vascular endothelial growth factor signaling pathway to suppress tumour angiogenesis89,90 Wang et al. demonstrated honokiol's nephroprotective effects against cisplatin-induced renal toxicity. This protection is mediated through dual mechanisms involving ROS generation suppression to maintain cellular redox homeostasis and cytoskeletal architecture-mediated stabilization of intercellular junction proteins, collectively mitigating cisplatin-mediated renal damage.91 Mechanistically, honokiol concurrently blocks caspase-3/9 driven apoptosis, inhibits NLRP3, and forms a coordinated regulatory network involving metabolic, apoptotic, and inflammatory pathways. While honokiol modulates apoptotic pathways via caspase-3/9 suppression (Fig. 5), its otoprotective potential through cochlear cytoskeletal stabilization remains uncharacterized, highlighting a critical research gap. Future studies should investigate whether Honokiol's cochlear cytoskeletal maintenance contributes to its otoprotective effects, representing a promising direction for further research.92

3.4. Stilbenes

Stilbenes, a class of natural polyphenolic phytochemicals, are predominantly found in plant parenchymatous tissues. They function as phytoalexins through activation of stilbene synthase-encoding genes, enabling plants to counteract environmental stressors.93,94 Importantly, stilbenes demonstrate significant pharmacological potential as inhibitors of microtubule dynamics.95 Capitalizing on their unique structural configurations, researchers have developed numerous synthetic stilbene derivatives that find broad applications across interdisciplinary domains, including chemical sciences, biological research, materials engineering, pharmaceutical development, and physical sciences (Fig. 8).

Fig. 8. Stilbenes monomers from traditional Chinese medicine to alleviate the ototoxicity of cisplatin.

Fig. 8

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3.4.1. Resveratrol

Resveratrol, a polyphenolic phytochemical predominantly isolated from Vitis species, demonstrates potent inhibitory effects on hepatocellular carcinoma cell migration, invasion, and epithelial–mesenchymal transition (EMT) progression.96 Emerging evidence extends its pharmacological profile to novel therapeutic applications beyond conventional antitumor activities, including multidrug resistance reversal, and otoprotection, which also highlights its unique mechanistic value in auditory toxicity intervention.97 Şimşek et al. demonstrated that intratympanic co-administration resveratrol and dexamethasone markedly reduced cisplatin ototoxicity in rats, with robust otoprotective effects.98 Notably, cochlear protection manifested in a dose-dependent manner, with the low-dose regimen (1 mg kg−1) demonstrating optimal therapeutic outcomes. This effective dosage enhanced the inner ear's antioxidant defense capacity through upregulation of cytochrome P450 family 1 subfamily A member 1 (CYP1A1), thereby partially ameliorating cisplatin-associated auditory dysfunction (Fig. 7). Although there is a paucity of literature directly investigating CYP1A1 and cisplatin ototoxicity, direct evidence suggests that CYP1A1 may exacerbate cisplatin-induced damage to auditory cells through ROS generation, and inflammatory signaling, but further experimental validation of its direct evidence in ototoxicity is still required.99 Conversely, the high-dose group (50 mg kg−1) failed to exhibit protective effects, suggesting that dose-dependent oxidative stress modulation underlies its mechanistic basis.100 Mechanistic studies elucidate that resveratrol mediates otoprotection via dual pharmacological mechanisms. Primarily, it modulates cytochrome P450 system activity in dose-dependent manner, participating in cisplatin metabolic processing and detoxification pathways. Secondarily, as a prototypical plant polyphenol, resveratrol demonstrates direct ROS scavenging activity. This neutralizes excess ROS generated during cisplatin exposure while concurrently suppressing apoptotic cascade activation in HEI-OC1 auditory cells.101 This distinctive antioxidant-detoxification synergistic mechanism distinguishes resveratrol as a premier candidate among stilbenes for combating cisplatin-associated ototoxicity. Convergent experimental evidence unequivocally establishes resveratrol's pivotal role in otoprotection through a multi-mechanistic framework involving coordinated modulation of CYP1A1-mediated antioxidant pathways, attenuation of ROS accumulation, and enhancement of cisplatin metabolic detoxification. The observed low-dose efficacy provides critical insights for clinical dosage optimization and establishes a foundational platform for developing novel otoprotective therapeutics (Fig. 8).

Fig. 7. Mechanism of stilbenes compounds to attenuate cisplatin ototoxicity.

Fig. 7

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4. Limitations and future development of natural polyphenols for cisplatin ototoxicity protection

4.1. Key limitations and barriers to clinical translation

Despite promising preclinical findings, the translation of natural polyphenols for cisplatin otoprotection is hampered by several key limitations and translational barriers that must be critically addressed. These include the very issues highlighted in the available literature, such as poor bioavailability and a scarcity of clinical validation. A primary challenge is the severely limited pharmacokinetic properties of these compounds. Polyphenols are generally characterized by low oral bioavailability, rapid metabolism, and insufficient systemic exposure, and are particularly difficult to efficiently penetrate the blood-vessel barrier.102 Furthermore, individual differences also play an important role in the pharmacokinetics and efficacy of polyphenolic compounds. For instance, genetic and epigenetic factors can affect the absorption and distribution characteristics of polyphenolic compounds, leading to significant variations in blood and tissue exposure levels among individuals. This means that even at the same dosage, different individuals may respond quite differently to polyphenolic compounds, thereby influencing their otoprotective effects.103 Although intratympanic injections can deliver drugs locally to circumvent BLB restrictions, the procedure is invasive, may induce middle ear inflammation or infection, and has low clinical maneuverability.15,104,105 Second, there is weak evidence of clinical translation and a lack of standardized protocols. Existing data on protective effects are mainly derived from rodent models, and there is a paucity of clinical trials in humans.106 In addition, cisplatin ototoxicity was dose cumulative.107 In contrast, no consensus has been established on the timing of polyphenol intervention, optimal dosage and duration of therapy, making it difficult to match the needs of individualized chemotherapy regimens. Finally, a significant concern is that the strong antioxidant effect of polyphenols may antagonize the tumour cell killing effect of cisplatin mediated by ROS, and there is a theoretical risk of weakening anticancer efficacy.108 Meanwhile, cisplatin itself has significant nephrotoxicity and needs to be supplemented with hydration therapy, while polyphenol metabolism may increase the burden of hepatic and renal function, which needs to be evaluated with caution especially in pediatric or elderly patients.109 Therefore, although natural polyphenols are mechanistically attractive, their path to clinical application is currently obstructed by low delivery efficiency, insufficient clinical evidence, incomplete mechanistic coverage and high translational barriers.

4.2. Future directions for natural polyphenol compounds

Based on the existing research, the future development of polyphenols will focus on the following directions, firstly, the development of intelligent delivery systems, the construction of functionalized nanocarriers (e.g., blood-labyrinthine barrier-penetrating liposomes), the enhancement of inner-ear targeting through the surface modification of transferrin receptor antibodies; the design of colonic localized release systems, the use of pH-responsive polymers to protect polyphenols from degradation by gastric acid, and the synchronization of enhanced intestinal absorption and localized bioactivity.110,111 Secondly, the pharmacokinetic properties of natural polyphenolic compounds can be optimized through chemical modifications (e.g. glycosylation, acetylation) and extended-release formulation development.112

As for the lack of human experiments mentioned above, a cross-scale clinical validation system can be established, using organoid models to simulate the microenvironment of the human inner ear, replacing traditional animal experiments to improve prediction accuracy, and conducting multi-center, adaptive clinical trials to dynamically adjust the polyphenol intervention protocol according to the cumulative dose of cisplatin, enhancing the potential for future clinical translation. As for the possible interference with cisplatin's anticancer activity, we have developed polyphenol-metal chelator hybrid molecules (e.g., quercetin-desferrioxamine coupling), which can scavenge free radicals and block the binding of cisplatin to DNA of the hair cells, and explored the sequential dosing scheme with sodium thiosulfate, which can inhibit the early oxidative damage of polyphenols, and neutralize the late accumulation of platinum ions with sodium thiosulfate, to minimize the inhibitory effect of polyphenols on the anticancer effect.

5. Conclusions

Natural products have historically served as a cornerstone for innovative drug discovery and development, approximately 60% of the global population depends on herbal remedies and natural medicines for disease management. Among these compounds, nature polyphenols occupy a prominent position in food, pharmaceutical, and nutraceutical applications, driven by their broad-spectrum anti-inflammatory and antioxidant properties. These characteristics position polyphenolic compounds as promising candidates for therapeutic development, offering a rich reservoir of bioactive molecules for both preventive and curative medicine.

Regarding cisplatin-induced ototoxicity, recent studies have focused on four main classes of polyphenol monomers, with flavonoids emerging as a particularly important subclass warranting further investigation. Mechanistic analyses reveal distinct therapeutic pathways: Quercetin demonstrates ROS reduction in cochlear hair cells through JNK pathway activation; EGCG exerts protective effects via STAT1 inhibition; and curcumin achieves dose-dependent mitigation of lipid peroxidation damage in cochlear tissues through modulation of the NRF2-OH-1 signaling axis. Phenolic acids and lignans also demonstrate measurable otoprotective efficacy, through with comparatively reduced potency relative to flavonoids. GA exerts otoprotective effects through free radical scavenging mechanisms, while the lignan compound silymarin provides protection via suppression of cochlear cell apoptotic cascades. Stilbenes, exemplified by resveratrol, despite being less extensively investigated, exhibit potent dual antioxidant and anti-inflammatory capacities. Mechanistic analyses across reveal a tripartite therapeutic paradigm: antioxidant activity involving free radical neutralization and ROS reduction to mitigate oxidative stress; anti-inflammatory action through modulation of inflammatory mediator expression; and anti-apoptotic protection via apoptotic pathway regulation. Central to these mechanisms are the Nrf2/Keap1 signaling axis and the Nrf2/GPX4 ferroptosis pathway, wherein oxidative stress induction ultimately triggers lipid peroxidation cascades culminating in cellular ferroptosis.

Notably, tetravalent platinum prodrugs offer a promising strategy to overcome limitations of classical platinum therapies. Preclinical studies demonstrate that cisplatin-polyphenol conjugates maintain potent antitumor activity while substantially reducing ototoxicity compared to conventional platinum agents, positioning them as safer next-generation alternatives for oncological treatment.

Despite significant advances in basic research, translating these findings into reliable clinical applications remains a formidable challenge. The poor pharmacokinetic properties of natural polyphenols, including low water solubility, poor absorption, and rapid metabolism, represent major bottlenecks limiting their clinical efficacy. More critically, their broad-spectrum antioxidant activity may non-selectively antagonize cisplatin's cytotoxic anticancer mechanisms, a potential risk that constitutes a core scientific issue that must be resolved prior to clinical translation.

Therefore, future research must move beyond preliminary mechanistic exploration to focus more on practical translational strategies. First, advanced drug delivery systems should be developed, such as encapsulating polyphenols in nanocarriers including liposomes, polymeric nanoparticles, or exosomes, to improve their water solubility, stability, and targeted enrichment in the inner ear, thereby enhancing bioavailability and therapeutic efficacy. Second, molecules such as tetravalent platinum-polyphenol conjugates can be constructed to achieve “integrated” anticancer activity and otoprotection, realizing synergistic efficacy and reduced toxicity within a single molecular entity. Additionally, polyphenol-metal chelator hybrid molecules with both antioxidant and metal-chelating functions can be designed to specifically block cisplatin's toxic reactions in healthy cochlear cells through their chelating capacity, without interfering with its anticancer effects in tumor cells (Table 1).

Table 1. Natural polyphenolic compounds mitigating cisplatin ototoxicity.

Name Principle Dosage Experimental model Cisplatin regimen Mechanisms/pathways Ref.
Quercetin Attenuates cisplatin-induced mitochondrial dysfunction and hair cell apoptosis 50 mg kg−1 Male adult Wistar rats 12 mg kg−1, single IP JNK signaling inhibition → suppression of mitochondrial apoptotic pathways 113
EGCG Reduces ROS generation and exerts anti-apoptotic effects Dose-dependent, best results at 150 μM Male adult Wistar rats (200–250 g) 11 mg kg−1, single IP STAT1 inhibition → increased STAT3/STAT1 ratio → cytoprotection 31
Curcumin Neutralizes ROS, inhibits lipid peroxidation, and enhances cochlear antioxidant defense 200 mg kg−1 is the most effective Male adult Wistar rats (200–250 g) 16 mg kg−1, single IP Nrf-2/HO-1 pathway activation → p53 phosphorylation downregulation 114
Puerarin Inhibits calcium overload and ROS-mediated cochlear apoptosis 200 mg kg−1 Adult C57BL/6 mice 16 mg kg−1, single IP TRPV1/IP3R1/p65 pathway blockade → reduced inflammatory signaling 115
Genistein Enhances antioxidant enzyme activity and reduces oxidative stress markers 10 mg kg−1 Male adult Wistar rats 16 mg kg−1, single IP SOD/CAT/GPX/TAC upregulation → redox homeostasis restoration 116
Nobiletin Inhibits ferroptosis in cochlear cells 20 μM dose is optimal Female Sprague–Dawley rats (200–300 g) 16 mg kg−1 q6h × 4 (IP) Autophagy activation → NRF2/GPX4-mediated ferroptosis suppression 117
Ferulic acid Reduces ROS accumulation and enhances endogenous antioxidant defenses 1.2 mM works best P4 C57BL/6 mice (e HEI-OC1 cells) 20 μM × 24 h PARP/Nrf2 pathway activation → pro-apoptotic gene downregulation 63
Caffeic acid Scavenges free radicals and inhibits inflammatory/apoptotic cascades 50 mg mL−1 House ear institute-organ of Corti 1 (HEI-OC1) cell 30 μM × 24 h Nrf2/HO-1 activation → NF-κB/IL-1β inhibition → RIPs-mediated apoptosis blockade 73, 118
Gallic acid Improves redox balance via ROS neutralization 100 mg kg−1 HEI-OC1 cells 20 μM × 24 h MDA reduction → SOD/GPx activity modulation 79, 118
Silymarin Attenuates cell cycle arrest and pro-apoptotic protein expression 50 mM Female Sprague–Dawley rats 15 mg kg−1, single IP Apoptotic cascade inhibition (Bcl-2/Bax ratio modulation → caspase-3/7/9 suppression) 86
Honokiol Eliminates mitochondrial ROS accumulation 5–25 μM effective, 10 μM maximum efficacy Adult C57BL/6 mice 15 mg kg−1, single IP SIRT3 activation → enhanced mitochondrial antioxidant capacity 119
Resveratrol Reduces oxidative stress and inflammatory factor expression 1–50 mM is toxic to cochlear cells, 1 mM is most effective HEI-OC1 auditory cells 15 μM × 24 h CYP1A1/RAGE-mediated antioxidant responses → NF-κB/IL-6/IL-2β suppression 101, 120
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In conclusion, future research priorities should shift from “confirming whether polyphenols are effective” to “how to make polyphenols more effective and safer for clinical use.” Only through breakthroughs in pharmaceutical sciences and synergistic drug design, followed by validation of safety and efficacy through carefully designed multicenter clinical trials, can we truly translate natural polyphenols from this valuable resource into first-line clinical strategies for protecting cancer patients' hearing.

Author contributions

Tong Wei: conceptualization, writing – original draft, writing – review & editing; Jing Nie: supervision, conceptualization, writing – review & editing; Dongbo Wang: writing – review & editing; Huina Wu: conceptualization, writing – review & editing; LiJiao Guan: resources, writing – review & editing.

Conflicts of interest

There are no conflicts to declare.

Acknowledgments

We thank the National Administration of Traditional Chinese Medicine (GZY-KJS-SD-2023-061) for financial support. Fig. 1, 3, 5 and 7 were Created in https://BioRender.com.

Data availability

No primary research results, software or code has been included and no new data were generated or analyzed as part of this review.

Notes and references

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