Small Molecule Therapeutic Approaches With a Greater Focus on Hearing Loss: A Review

ABSTRACT

Background and Aims

Hearing loss (HL) is one of the most common sensory impairments worldwide and has substantial effects on quality of life and daily functioning. Although cochlear implants and hearing aids have markedly improved the management of hearing impairment, these devices do not directly address the underlying pathogenic mechanisms of HL. This review aims to summarize the pathophysiology and classification of HL and to discuss the potential therapeutic applications of small molecules (SMs) in its management.

Methods

This review focuses on the major pathological mechanisms involved in different forms of HL and summarizes preclinical and clinically relevant SM‐based therapeutic approaches. The reviewed strategies include pharmacological chaperones, transcriptional modulation, ion‐channel modulators, neuroprotective compounds, apoptosis inhibitors, and regenerative approaches.

Results

SMs possess physicochemical properties that make them suitable for targeting specific molecular pathways involved in HL. Current evidence suggests that SM‐based interventions may act through diverse mechanisms, including attenuation of oxidative stress, inflammation, and apoptosis; modulation of ion channels; support of auditory neuron survival and function; and promotion of regenerative signaling.

Conclusion

SM‐based therapeutic approaches represent promising strategies for addressing the molecular and cellular mechanisms underlying HL. These approaches may provide valuable directions for future research and support the development of targeted therapies for individuals with hearing impairment.

1. Introduction

Hearing loss (HL) is a significant global health challenge with profound socioeconomic implications. According to recent estimates by the World Health Organization (WHO), over 1.5 billion people worldwide—nearly 20% of the global population—live with some degree of HL. Of these, approximately 430 million individuals require rehabilitation services for disabling HL, a figure projected to rise to over 700 million by 2050 unless effective interventions are implemented (https://www.who.int/news-room/fact-sheets/detail/deafness-and-hearing-loss). Current understudied strategies intended for the treatment and management of HL include a variety of therapies that focus on the particularities of the functioning of the auditory system and the nature of the pathological processes of HL. Indeed, the main strategies for HL management that have been primarily employed over the years, viewed globally, include hearing aids and cochlear implants, which are basically devices designed to amplify and restore sound perception by bypassing the damaged components of the auditory pathway However, these devices primarily improve auditory function and do not repair the underlying pathology of HL [1].

To develop effective treatment techniques, it is necessary to have a comprehensive understanding of the complex pathophysiology that underlies the various forms of HL. Its treatment is now evolving in several innovative approaches. Researchers are investigating gene therapy as a potential approach to directly transfer genetic material into the inner ear in order to assist individuals with hearing impairments in repairing or improving their hearing [2]. This might include concentrating on genes involved in the development and regeneration of hair cells or introducing genes that enhance the survival and function of existing hair cells [3]. Stem cell treatment is a novel approach being investigated by scientists now that uses pluripotent stem cells. This therapy aims to create supporting and inner ear hair cells. The intended procedure involves the transplantation of specialized cells into the damaged cochlea in order to regenerate hair cells that have been destroyed or rendered nonfunctional [4]. In parallel, scientists are now developing many drug cures. They are searching through libraries of small molecule (SM) substances to find new treatments that might either prevent the loss of hearing cells or promote their regeneration [1].

SM drugs have played a central role in modern pharmacotherapy since the late 19th and early 20th centuries [5]. SM therapeutics have been investigated across a broad range of diseases. In particular, studies in neurological disorders, cancer, and inflammatory conditions have highlighted their translational potential and versatility [6, 7, 8]. Indeed, SMs are organic compounds having a molecular weight usually less than 900 Daltons. They have unique physical and chemical properties that make them attractive for developing new therapies for hearing disorders [9]. These compounds with low molecular weight have the ability to pass through biological barriers, interact with specific molecular targets, and selectively modify signaling pathways [5]. While a number of studies have examined categories of SM approaches, the present manuscript provides a different perspective. Moreover, HL has not been specifically emphasized in previous discussions, despite the numerous studies published on therapeutic SMs for various diseases.

This review aims to provide a focused overview of SM‐based therapeutic approaches, emphasizing their mechanisms of action across different disease contexts and their potential relevance to HL. Lastly, we investigate the present condition of available SMs and the prospect of clinical trials for SM‐based treatments in addressing HL. The objective offers a helpful reference for researchers, doctors, and others interested in the treatment of HL.

2. Hearing Loss Pathophysiology

Development of targeted therapy strategies depends on an understanding of the underlying pathophysiology of various forms of HL. An outline of the main processes and routes contributing to the development of HL is given in this subsection.

2.1. Sensorineural Hearing Loss

Most occurrences of HL are sensory in nature, which is mostly brought on by damage or dysfunction of the inner ear, most especially the cochlea and auditory nerve [10]. Sensorineural HL causes are the following main mechanisms:

• Hair Cell Damage and Death: The main transducers of sound, the sensory hair cells in the cochlea transform mechanical vibrations into electrical impulses. Whether from hereditary causes, noise exposure, ototoxic medications, or aging, these hair cells can be damaged or lost. Dysfunction and death of hair cells can result from factors including apoptosis, excitotoxicity, and oxidative stress [11].

• Auditory Nerve Degeneration: Sensorineural HL can also result from damage or degeneration of the auditory nerve, which carries the electrical impulses from the hair cells to the central auditory system. This could be brought on by neurodegenerative diseases, trauma, ischemia, or demyelination [12].

• Strial Atrophy and Metabolic Dysfunction: Hair cell function depends on the stria vascularis, a specific structure inside the cochlea, to preserve the ionic composition and endocochlear potential. Alterations to ion homeostasis and metabolic abnormalities brought on by age‐related or pathological alterations in the stria vascularis can eventually compromise hair cell transmission [13].

• Oxidative Stress and Mitochondrial Dysfunction: Several forms of sensorineural HL have been linked to pathogenesis via increased synthesis of reactive oxygen species and compromised mitochondrial function. Within the inner ear, hair cells, auditory neurons, and supporting structures can all be directly impacted by oxidative damage [14].

2.2. Conductive Hearing Loss (CHL)

CHL occurs when sound transmission through the external or middle ear is impaired, thereby reducing the efficiency with which acoustic energy reaches the cochlea. This form of HL usually results from abnormalities involving the external auditory canal, tympanic membrane, or ossicular chain [15, 16]. Disorders of the external ear commonly include cerumen impaction, foreign bodies, and structural or inflammatory abnormalities of the external auditory canal, all of which may obstruct sound conduction to the tympanic membrane [15, 17]. In addition, middle ear conditions such as otitis media with effusion, tympanic membrane abnormalities, and ossicular pathology can interfere with mechanical sound transmission and produce conductive HL [15, 16]. Depending on the etiology, CHL may resolve with medical treatment or require surgical intervention [15].

2.3. Mixed Hearing Loss

Mixed HL is a hybrid of conductive and sensorineural HL in which the sound transmission channel and the peripheral auditory system are both affected by the underlying disorder [18].

Understanding the complex and multifaceted pathophysiology of HL is essential for the development of effective therapeutic strategies. However, although different forms of hearing impairment are associated with distinct underlying mechanisms, accurate identification of the precise pathophysiology in individual patients remains challenging in current clinical practice. In most cases, available diagnostic tools can classify HL broadly as sensorineural, conductive, or mixed, but they do not reliably determine the exact cellular or molecular lesion responsible for the deficit. Exceptions exist in selected conditions, such as auditory neuropathy spectrum disorder and certain genetically defined forms of HL, in which the underlying mechanism can be more specifically inferred. Therefore, while mechanism‐based therapies represent a promising direction, their clinical implementation will depend on further advances in diagnostic precision. The pathophysiology of HL and the anatomical structure of the ear are briefly summarized in Figure 1.

Figure 1.

(a) A brief description of the pathophysiology of HL, (b) Schematic representation of auditory anatomy (1) Sound waves entering the external ear induce vibration of the tympanic membrane, which is transmitted through the middle‐ear ossicles to the inner ear. (2) Cross‐sectional schematic of the cochlear duct and organ of Corti, illustrating the relative positions of the Reissner's membrane, stria vascularis, basilar membrane, tectorial membrane, inner and outer hair cells, and supporting cells. Sound‐induced pressure waves in the cochlear fluids produce basilar membrane vibration and relative motion between the basilar and tectorial membranes. This mechanical motion deflects the hair‐cell stereocilia, leading to opening of mechanoelectrical transduction (MET) channels, hair‐cell depolarization, and subsequent auditory signaling. (3) Damage to cochlear hair cells caused by aging, noise exposure, genetic factors, or ototoxic agents can contribute to sensorineural HL. (generated using Wondershare EdrawMax application). All content, labels, and scientific representations were reviewed and verified by the authors, who take full responsibility for the accuracy and integrity of the figure.

3. General Small Molecule Therapeutic Approaches

SMs have become a multipurpose class of therapeutic agents with a variety of approaches for influencing different biological pathways and processes. In this section, we shall discuss the different SM approaches that have been investigated in previous studies.

3.1. Pharmacological Chaperones

Pharmacological chaperones are SMs that selectively bind to misfolded or unstable proteins and stabilize their conformation, thereby facilitating proper folding, trafficking, and function. This strategy is particularly relevant for genetic disorders caused by missense mutations that lead to protein misfolding and subsequent degradation. By stabilizing these mutant proteins, pharmacological chaperones can partially restore their activity and improve cellular function [19].

For instance, Migalastat is a pharmacological chaperone utilized in the treatment of Fabry disease. It functions by binding to and stabilizing specific mutant forms of alpha‐galactosidase A, thereby facilitating their correct folding and lysosomal trafficking [20]. However, the therapeutic efficacy of Migalastat is highly dependent on the patient's specific genotype, as the drug is effective primarily in patients harboring ‘amenable’ mutations that allow for protein stabilization and subsequent rescue of enzymatic activity [20, 21, 22]. Other example is Ambroxol as a pharmacological chaperone used for the treatment of Gaucher disease, a rare genetic disorder caused by the deficiency of the enzyme beta‐glucocerebrosidase. Ambroxol binds to and stabilizes the mutant form of the beta‐glucocerebrosidase enzyme, promoting its proper folding and trafficking to the lysosomes [23]. Pendred syndrome provides a hearing‐related example of this strategy. SLC26A4 encodes pendrin, a membrane anion transporter involved in maintaining the ionic composition of the inner‐ear endolymph. Some disease‐associated missense variants, including P123S, exhibit defective intracellular trafficking, resulting in reduced localization of pendrin at the plasma membrane. In a cell‐based model expressing P123S mutant pendrin, the SM (2‐aminophenyl) methanol promoted the trafficking of the mutant protein toward the plasma membrane, thereby increasing its membrane localization, and was proposed as a candidate molecular chaperone for Pendred syndrome [24]. These findings provide proof of concept that chaperone‐mediated rescue of mutant protein trafficking may have therapeutic relevance to hearing disorders, although an improvement in auditory function has not yet been demonstrated in vivo.

3.2. Transcriptional Modulation Strategies

Transcriptional regulation can be modulated by SMs through several distinct mechanisms. These include direct targeting of ligand‐activated transcription factors (TFs), disruption of transcriptional cofactor interactions, inhibition of epigenetic regulators, interference with the transcriptional elongation machinery, modulation of signaling pathways that control transcriptional outputs, and regulation of non‐coding RNA biogenesis or function.

• ▪Targeting ligand‐activated TFs: SMs can directly bind TF families such as nuclear receptors and alter their transcriptional activity. A landmark example is retinoic acid, which signals through retinoic acid receptors (RARs) to regulate gene expression [25]. Likewise, dexamethasone modulates transcription through the glucocorticoid receptor (GR), consistent with experimentally demonstrated transcriptional regulation of the GR axis [26].
• ▪Targeting transcriptional coregulators: SMs can disrupt transcription‐associated protein–protein interactions and chromatin recognition events. BET bromodomain inhibitors are representative examples, as they block bromodomain‐containing proteins such as BRD4 from recognizing acetylated lysine residues and thereby impair transcriptional coactivation [27].
• ▪Modulating epigenetic mechanisms: SMs can inhibit epigenetic enzymes that regulate chromatin state and gene expression. Vorinostat is a histone deacetylase (HDAC) inhibitor with experimentally demonstrated antitumor activity [28], whereas 5‐azacytidine can reverse aberrant DNA methylation and restore gene expression in cancer cells [29].
• ▪Interfering with the transcriptional machinery: Some SMs suppress transcription by inhibiting kinases required for RNA polymerase II elongation. Flavopiridol, for example, inhibits CDK9/P‐TEFb‐dependent phosphorylation of the RNA polymerase II C‐terminal domain, thereby reducing transcription [30].
• ▪Modulating signaling pathways: SMs can also alter transcription indirectly by targeting upstream signaling pathways that govern TF activity. For example, trametinib suppresses MEK/ERK pathway output and has been shown to silence BRAF–MEK–ERK‐dependent transcriptional programs in malignant cells [31].
• ▪Targeting non‐coding RNAs: SMs have also been developed to regulate non‐coding RNAs, including oncogenic microRNAs. For instance, drug‐like SMs that inhibit the expression of miR‐21 have been described in primary research studies [32].

Together, these mechanisms illustrate how SMs can selectively reprogram transcriptional states and support therapeutic intervention across diverse disease contexts.

3.3. Ion Channel Modulators

SMs serve as critical ion channel modulators, regulating the selective transport of ions across cellular membranes to maintain physiological homeostasis [33]. These modulators are generally classified based on their target channel's gating mechanism:

3.3.1. Voltage‐Gated Ion Channels (VGICs)

SMs can bind to specific pore‐forming subunits or auxiliary domains to inhibit or enhance ion conductance in response to membrane potential changes [33, 34]. For instance, 4‐aminopyridine is a non‐selective potassium channel (K_V) blocker used clinically to improve nerve conduction in demyelinating conditions [35]. Additionally, dihydropyridines like nifedipine are prototypical l‐type calcium channel blockers (Ca_V) widely used in treating hypertension and angina [36].

In the auditory system, voltage‐gated potassium channels are particularly important for maintaining cochlear hair‐cell function. KCNQ4 (Kv7.4) contributes to the potassium current required for maintenance of the resting membrane potential and repolarization of outer hair cells (OHCs). Loss or dysfunction of KCNQ4 causes chronic OHC depolarization and progressive OHC degeneration and is associated with DFNA2‐related progressive HL [37]. Accordingly, pharmacological activation of Kv7.4 represents a hearing‐relevant ion‐channel strategy. In vivo activation of Kv7.4 has been shown to reduce age‐related auditory threshold shifts and OHC loss in a mouse model of age‐related HL [38].

3.3.2. Ligand‐Gated Ion Channels (LGICs)

These channels open upon the binding of specific chemical messengers and are highly susceptible to modulation by SMs [39]. Benzodiazepines are well‐characterized positive allosteric modulators of GABA_A receptors, enhancing chloride influx to produce sedative and anxiolytic effects [40, 41]. Conversely, nicotine acts as a direct exogenous agonist of nicotinic acetylcholine receptors (nAChRs), which are cation‐selective LGICs involved in neuromuscular and cognitive signaling [42].

3.3.3. Transient Receptor Potential (TRP) Channels

TRP channels function as polymodal sensors for various physical and chemical stimuli. SMs such as capsaicin (a TRPV1 agonist) and menthol (a TRPM8 agonist) are classic examples used to study and treat sensory‐related disorders, including chronic pain and thermal hypersensitivity [43].

3.3.4. Two‐Pore Domain Potassium (K_2P) Channels

K_2P channels (leak channels) are essential regulators of resting membrane potential and cellular excitability [44]. Their activity is modulated by various pharmacological agents; for example, volatile anesthetics like halothane activate TREK‐1 channels, whereas local anesthetics such as bupivacaine can inhibit them, contributing to their anesthetic profile [45, 46].

3.3.5. Ionotropic Glutamate Receptors

As the primary mediators of excitatory neurotransmission, these receptors (NMDA, AMPA, and Kainate) are major targets for SM modulators [47]. Ketamine and memantine serve as clinically significant N‐methyl‐d‐aspartate (NMDA) receptor antagonists, each possessing distinct therapeutic profiles. Ketamine acts as a non‐competitive NMDA receptor antagonist, widely utilized in anesthesia and as a rapid‐acting intervention for treatment‐resistant depression (TRD) [48]. Conversely, memantine functions as a low‐to‐moderate affinity, uncompetitive NMDA receptor antagonist, primarily indicated for the symptomatic management of moderate‐to‐severe Alzheimer's disease [49].

3.3.6. Purinergic P2X Receptors

Purinergic signaling, particularly through ionotropic P2X receptors, is involved in diverse processes from inflammation to pain [50]. P2X receptors are trimeric ligand‐gated cation channels activated by extracellular ATP, which serves as their endogenous agonist [51].

3.4. Neuroprotective Compounds

Whereas Section 3.3 classifies SMs primarily according to their direct molecular targets, this section focuses on the downstream protective effects that may result from modulation of these targets. Neuroprotective SMs can preserve neuronal viability through multiple mechanisms, including attenuation of oxidative stress, excitotoxicity, and neuroinflammatory responses. Edaravone, a free‐radical scavenger, has shown therapeutic benefit in acute ischemic stroke by reducing oxidative injury associated with cerebral infarction [52, 53]. Memantine, discussed above as an NMDA receptor antagonist, illustrates this distinction: its direct molecular action is blockade of NMDA receptor‐mediated responses, whereas the resulting functional effect is protection against excitotoxic neuronal injury [54]. Minocycline has also demonstrated neuroprotective effects by reducing inflammation and protecting against focal cerebral ischemic injury [55]. Oxidative stress is also a particularly relevant target for neuroprotective and otoprotective SM strategies in HL. Acoustic overexposure and ototoxic insults can increase the production of reactive oxygen species and other free radicals in the cochlea, promoting oxidative damage, mitochondrial dysfunction, and activation of cell‐death pathways in sensory hair cells [56]. Experimental evidence has demonstrated cochlear oxidative stress following noise exposure in vivo and its reduction following antioxidant intervention [56]. Thus, SMs that reduce oxidative stress or enhance endogenous antioxidant defenses provide a mechanistic strategy for limiting cochlear injury and preserving auditory function. Together, these original experimental and clinical findings support the clinical applicability of neuroprotective SMs through complementary antioxidant, anti‐excitotoxic, and anti‐inflammatory mechanisms.

3.5. Apoptosis Inhibitors

SM apoptosis inhibitors are designed to prevent programmed cell death and promote cellular survival by interfering with key signaling pathways involved in apoptotic regulation. Apoptosis is primarily mediated through intrinsic (mitochondrial) and extrinsic signaling pathways that converge on the activation of caspase proteases, ultimately leading to cellular dismantling [57]. Several classes of SMs can suppress apoptosis by targeting different components of these pathways. Direct caspase inhibitors, such as z‑VAD‑fmk, block the proteolytic activity of executioner caspases and thereby prevent the downstream events of apoptotic cell death [58]. Other compounds act at the mitochondrial level by stabilizing mitochondrial membrane integrity and preventing mitochondrial outer membrane permeabilization, a critical step in cytochrome c release and apoptosome formation [59]. Additional strategies involve modulation of regulatory proteins that control apoptotic signaling. SM may enhance the activity or expression of anti‑apoptotic Bcl‑2 family proteins or inhibit pro‑apoptotic proteins such as Bax and Bak, thereby maintaining mitochondrial stability [60]. Furthermore, some compounds regulate upstream stress responses by modulating the activity of the tumor suppressor p53 or by influencing autophagic pathways that interact with apoptotic signaling networks [61]. Collectively, these approaches highlight the therapeutic potential of SM apoptosis inhibitors in conditions where excessive cell death contributes to tissue damage.

3.6. Regenerative Strategies

SMs can play an important role in regenerative strategies by modulating key cellular processes involved in tissue repair and regeneration. These compounds can influence stem cell proliferation and differentiation, promote cellular reprogramming, and regulate signaling pathways that control tissue regeneration [62]. For example, inhibitors of glycogen synthase kinase‑3 (GSK‑3), such as CHIR99021, activate the Wnt/β‑catenin pathway and enhance stem cell proliferation and regenerative responses [63]. Histone deacetylase inhibitors such as valproic acid can modulate epigenetic states and facilitate cellular reprogramming and differentiation [64]. In addition, several SMs have been shown to improve the regenerative microenvironment by modulating angiogenesis, inflammatory responses, extracellular matrix remodeling, and fibrotic processes. For instance, the Wnt/β‐catenin inhibitor ICG‐001 has been reported to attenuate fibrosis and enhance tissue repair, while activation of pro‐angiogenic signaling pathways by specific SMs can stimulate neovascularization and support tissue regeneration [65, 66]. These effects collectively contribute to creating a favorable microenvironment for functional tissue repair and regeneration.

The versatility of SM approaches (Figure 2) allows for targeted intervention in diverse biological systems and disease contexts, making them a valuable tool in the arsenal of therapeutic strategies.

Figure 2.

A comprehensive schema of therapeutic SM approaches (generated using Wondershare EdrawMax application). All content, labels, and scientific representations were reviewed and verified by the authors, who take full responsibility for the accuracy and integrity of the figure.

4. Small Molecule Therapeutics for Hearing Loss

In recent years, significant progress has been made in the development of SM therapeutics that hold promise in the prevention and treatment of HL. These SM compounds target various pathways and mechanisms involved in the pathogenesis of hearing impairment, offering new avenues for therapeutic intervention.

4.1. d‐Methionine

D‑Methionine is a sulfur‑containing amino acid that has demonstrated significant otoprotective effects in both experimental and preclinical studies. Its protective activity is primarily attributed to its ability to counteract oxidative stress within the cochlea [67]. D‑Methionine contributes to the maintenance of intracellular redox balance by enhancing glutathione synthesis and scavenging reactive oxygen species (ROS), thereby reducing lipid peroxidation and mitochondrial damage in cochlear tissues [68]. These effects are particularly important in protecting outer hair cells, which are highly susceptible to oxidative injury following acoustic trauma or exposure to ototoxic agents such as cisplatin [67, 68]. In addition to its antioxidant activity, D‑Methionine has been reported to modulate inflammatory responses and inhibit apoptosis in cochlear cells by reducing caspase activation and mitochondrial stress pathways [69]. Through these mechanisms, D‑Methionine helps preserve hair cell integrity and maintain auditory threshold levels in models of noise‑induced and drug‑induced HL [70]. Several preclinical studies and early clinical investigations have therefore suggested that D‑Methionine may serve as a promising SM therapeutic candidate for the prevention of cochlear injury and HL [69].

4.2. N‐Acetylcysteine (NAC)

NAC is a thiol‐containing SM that has been investigated as an otoprotective agent in both cisplatin‐induced and noise‐induced HL. In cisplatin ototoxicity, cochlear glutathione depletion and free‐radical–mediated oxidative damage are considered important pathogenic mechanisms [71, 72]. In a rat cochlear culture model, NAC completely prevented cisplatin‐induced hair cell loss; in the same study, NAC also reduced mitochondrial ROS and abolished TUNEL‐positive hair cells in the co‐treatment group [73]. In addition to in vitro findings, various animal models have demonstrated the protective potential of NAC against cisplatin‐induced ototoxicity. Specifically, NAC administration has been shown to significantly attenuate permanent threshold shifts (PTS) as measured by auditory brainstem response (ABR) and preserve the structural integrity of cochlear hair cells, reducing the severe stereocilia damage typically observed after cisplatin exposure [72, 74]. In noise‐induced HL, a systematic review and meta‐analysis of randomized controlled trials suggested that NAC may reduce hearing‐threshold shifts, although larger trials were recommended [75]. However, a recent meta‐analysis of cisplatin‐induced HL did not show a significant benefit for NAC in the conventional audiometric range, despite a possible trend toward protection at ultra‐high frequencies [76]. Overall, NAC is best viewed as an antioxidant‐based SM whose main reported cochlear target is oxidative stress–related hair‐cell injury, while its clinical efficacy remains to be established.

4.3. Corticosteroids

Dexamethasone, a corticosteroid, has been used through both systemic and intratympanic routes in idiopathic sudden sensorineural HL (ISSNHL) [77]. In ISSNHL, systemic steroids are historically considered first‐line therapy, while intratympanic steroids are commonly employed as salvage treatment after insufficient recovery with systemic therapy. The proposed local mechanism of intratympanic dexamethasone is diffusion through the round window with reduction of inner‐ear inflammation [77]. Additional experimental evidence indicates that dexamethasone may also exert anti‐oxidative effects, because it has been described as a catalytic radical scavenger that counteracts oxidative stress [78]. At the cochlear level, dexamethasone has been investigated for protective effects on the organ of Corti, including inner hair‐cell stereocilia morphology [78]. In autoimmune inner ear disease (AIED), corticosteroids are used mainly via the systemic route, because glucocorticoids remain the first‐line therapy for this steroid‐responsive immune‐mediated hearing disorder [79]. Experimental and pathological observations in AIED indicate that immune injury may affect different cochlear compartments, including sensory and supporting cells in inflammatory cochlear lesions and the stria vascularis in autoimmune microvascular disease [79]. Therefore, the principal approach of corticosteroids is anti‐inflammatory/immunosuppressive therapy, and the main reported sites of action in the ear include the inner ear/cochlea, particularly inflammatory pathways involving the organ of Corti, and in some disease settings the stria vascularis.

4.4. Other Small Molecule Therapeutics

Beyond the compounds discussed above, several other SMs have been explored as candidate therapeutics for hearing disorders, acting through mechanisms such as neurotransmitter modulation, antioxidant or metabolic support, and ion‐channel regulation. These mechanisms correspond to key pathological features addressed in the examples below, including synaptic vulnerability, oxidative stress, mitochondrial dysfunction, and altered auditory excitability.

Piribedil, a dopamine D2 receptor agonist, has been investigated in noise‐related cochlear injury. Experimental work showed that piribedil blocked noise‐induced cochlear dopamine turnover, consistent with dopaminergic modulation within the cochlea [80]. In a later study, systemic piribedil, particularly when combined with memantine, reduced noise‐induced loss of inner hair cell synaptic ribbons, suggesting protection at the level of the IHC‐auditory nerve synapse [81].

Trimetazidine has been studied as an antioxidant SM in noise‐induced cochlear damage. In rabbits exposed to noise, trimetazidine preserved transient evoked otoacoustic emission parameters and attenuated oxidative stress‐related biochemical changes, including alterations in malondialdehyde, glutathione, glutathione peroxidase, and glutathione reductase. These findings support protection of cochlear function, particularly mechanisms related to outer hair cell integrity [82].

Coenzyme Q10 (ubiquinone) has been explored because of its role in mitochondrial electron transport and antioxidant defense. In preclinical models of cisplatin ototoxicity, CoQ10‐based treatment reduced HL and was investigated as a strategy to limit ROS‐mediated inner‐ear injury [83]. In a human study, treatment with the water‐soluble CoQ10 formulation Q‐Ter was associated with a shorter recovery time following experimentally induced noise‐related temporary threshold shift [84].

Retigabine (trobalt), a Kv7/KCNQ potassium‐channel opener, has been investigated in auditory disorders because potassium‐channel activity is important for auditory excitability. Current evidence more strongly supports its relevance to noise‐induced tinnitus and to the broader therapeutic concept of KCNQ4 activation in hearing disorders than to direct proof of hair‐cell rescue in noise‐induced HL [85].

4‐Phenylbutyrate (4‐PBA) is a SM with chaperone activity that has shown otoprotective effects in experimental models of HL. In Cdh23 ^erl/erl mutant mice, a model of progressive genetic HL, systemic treatment with 4‐PBA significantly alleviated HL and suppressed cochlear hair‐cell death, accompanied by downregulation of ER‐stress‐related proteins [86]. More recently, 4‐PBA was investigated as a pharmacological chaperone in a mouse model of noise‐induced PTS. In this model, reduction of CHOP expression by pharmacological chaperone treatment facilitated partial hearing recovery following PTS [87].

Tauroursodeoxycholic acid (TUDCA) is a SM with proteostasis‐promoting and chaperone activity that has demonstrated otoprotective effects in several experimental models of HL. In Cdh23 ^erl/erl mice, systemic TUDCA treatment significantly alleviated HL and suppressed cochlear hair‐cell death, together with inhibition of apoptotic signaling and caspase‐3 activation [88]. TUDCA has also been investigated in cisplatin‐induced ototoxicity. Both subcutaneous and transtympanic administration attenuated cisplatin‐induced increases in auditory brainstem response thresholds in rats, while mechanistic experiments showed reduced ER stress and apoptosis and inhibition of the accumulation and aggregation of unfolded or misfolded proteins [89]. Furthermore, TUDCA was evaluated as a pharmacological chaperone in the recent noise‐induced PTS model, in which chaperone treatment facilitated partial hearing recovery [87].

BF844 is a SM identified through screening for compounds capable of stabilizing the USH3‐associated mutant protein CLRN1^N48K. In a mouse model mimicking progressive USH3‐associated HL, BF844 significantly attenuated hearing deterioration and prevented deafness, supporting mutant‐protein stabilization as a potential SM strategy for genetically defined forms of HL [90].

Vorinostat, also known as suberoylanilide hydroxamic acid (SAHA), is a SM histone deacetylase (HDAC) inhibitor with otoprotective activity in experimental HL. In adult mice exposed to kanamycin and furosemide, systemic SAHA treatment markedly protected against cochlear hair‐cell loss and hearing‐threshold shifts [91]. Mechanistically, HDAC inhibition maintained acetylation of the TF RelA/p65 at K310 and promoted activation of the NF‐κB pro‐survival pathway, accompanied by increased expression of pro‐survival genes including Cflar and Bcl2l1 [91]. These findings support transcriptional and epigenetic modulation as a potential SM‐based strategy for protecting auditory hair cells from ototoxic injury.

4‐Diethylaminobenzaldehyde (DEAB) is a SM aldehyde dehydrogenase (ALDH) inhibitor that has been investigated as a transcription‐modulating strategy for DFNA15, a progressive form of HL associated with POU4F3 haploinsufficiency. Inhibition of retinoic acid signaling by DEAB increased cochlear Pou4f3 expression and upregulated its downstream target Lhx3 [92]. In Pou4f3 mutant mice, systemic DEAB treatment preserved auditory function, as assessed by auditory brainstem response and distortion‐product otoacoustic emission measurements, and improved outer hair‐cell survival [92]. These findings demonstrate that pharmacological upregulation of a hearing‐related TF may represent a potential therapeutic strategy for genetically defined progressive HL.

4.5. Emerging Small Molecule Therapeutics

Several SMs have been investigated as emerging therapeutic candidates for HL, mainly through otoprotective or regenerative mechanisms. Unlike the compounds discussed above, these agents represent newer translational approaches aimed at either preventing cochlear injury or promoting repair of the sensory epithelium.

Ebselen (SPI‐1005) is a glutathione peroxidase‐mimicking SM with antioxidant and anti‐inflammatory properties. It has shown protective effects in preclinical models of noise‐induced and aminoglycoside‐induced cochlear injury, and it has also advanced into clinical evaluation for inner‐ear disorders, including sensorineural HL, tinnitus, and other auditory conditions [93]. Its therapeutic rationale is based on limiting oxidative stress and inflammatory injury within the cochlea, two major contributors to sensory‐cell damage.

Sodium thiosulfate is an otoprotective SM that has been clinically evaluated for the prevention of cisplatin‐induced HL. In randomized pediatric trials, delayed administration of sodium thiosulfate after cisplatin reduced the incidence of HL, supporting its role as a clinically relevant protective agent against platinum‐related cochlear toxicity [94, 95]. Although its main application is prevention rather than restoration of established HL, it remains an important translational example of SM otoprotection.

FX‐322 is an intratympanic regenerative small‐molecule candidate composed of CHIR99021 and valproic acid, two compounds selected to activate cochlear progenitor‐associated regenerative pathways. It was developed to promote hair‐cell regeneration in stable sensorineural HL. In a phase 1b clinical study, intratympanic FX‐322 was generally well tolerated and was associated with improvement in speech‐intelligibility measures in a subset of treated subjects [96].

Another important SM program is represented by ORC‐13661, which emerged from the ORC chemical series. This compound protected zebrafish lateral‐line hair cells, mouse cochlear cultures, and rat hearing from aminoglycoside‐ and cisplatin‐induced injury. Mechanistically, ORC‐13661 acts as a high‐affinity permeant blocker of the hair‐cell mechanotransduction channel, thereby reducing ototoxin entry into sensory hair cells [97]. This mode of action makes the ORC series a notable example of rational SM otoprotection targeting a proximal step in hair‐cell injury.

The development of SM therapeutics for HL remains an active and evolving field, with potential applications in both otoprotection and auditory repair. These agents target diverse mechanisms implicated in hearing impairment, including oxidative stress, inflammation, ototoxic injury, synaptic dysfunction, neuronal excitability, and regenerative signaling. A summary of therapeutic SMs for HL and their proposed functions is provided in Table 1. While several compounds have demonstrated protective or restorative effects in preclinical and early clinical studies, further clinical validation is required to define their efficacy, safety, dosing strategies, and long‐term outcomes.

Table 1.

A summary of HL therapeutic SMs.

Small molecule therapeutic	Proposed mechanism/function	Hearing‐loss model or condition	Main reported effect/target site
d‐Methionine	Enhances glutathione synthesis, scavenges ROS, reduces lipid peroxidation and mitochondrial damage; modulates inflammation and apoptosis	Noise‐induced and drug‐induced HL, including cisplatin‐related cochlear injury	Protects cochlear tissues, especially outer hair cells; preserves hair‐cell integrity and auditory threshold levels
N‐Acetylcysteine (NAC)	Thiol‐containing antioxidant; reduces mitochondrial ROS, glutathione depletion, oxidative damage, and TUNEL‐positive hair cells	Cisplatin‐induced and noise‐induced HL	Prevents or attenuates hair‐cell loss and threshold shifts in experimental models; clinical efficacy remains to be established
Dexamethasone/corticosteroids	Anti‐inflammatory and immunosuppressive activity; possible catalytic radical‐scavenging and anti‐oxidative effects	ISSNHL and autoimmune inner ear disease	Acts in the inner ear/cochlea, including the organ of Corti and inflammatory pathways; may protect inner hair‐cell stereocilia morphology
Piribedil	Dopamine D2 receptor agonist; modulates cochlear dopamine turnover	Noise‐related cochlear injury	Reduces noise‐induced loss of inner hair‐cell synaptic ribbons, especially when combined with memantine
Trimetazidine	Antioxidant and metabolic support; attenuates oxidative stress‐related biochemical changes	Noise‐induced cochlear damage	Preserves transient evoked otoacoustic emission parameters and supports outer hair‐cell integrity
Coenzyme Q10	Supports mitochondrial electron transport and antioxidant defense	Cisplatin‐induced ototoxicity (preclinical); noise‐induced temporary threshold shift (human study)	Reduces ROS‐mediated inner‐ear injury in preclinical models; associated with shorter recovery time after noise‐induced temporary threshold shift in humans
Retigabine/Trobalt	Kv7/KCNQ potassium‐channel opener; regulates auditory excitability	Noise‐induced tinnitus and KCNQ‐related hearing‐disorder mechanisms	Supports the therapeutic concept of KCNQ4 activation; direct proof of hair‐cell rescue in noise‐induced HL remains limited
4‐Phenylbutyrate (4‐PBA)	Chaperone‐mediated modulation of protein homeostasis; reduces ER stress and pro‐apoptotic stress signaling	Cdh23 erl/erl genetic HL; noise‐induced PTS	Alleviates HL and hair‐cell death in Cdh23 erl/erl mice; pharmacological chaperone treatment facilitates partial hearing recovery after noise‐induced PTS
TUDCA	Chaperone/proteostasis modulation; reduces ER stress and apoptosis	Cdh23 erl/erl genetic HL; cisplatin‐induced HL; noise‐induced PTS	Alleviates HL and hair‐cell death; attenuates ototoxic threshold elevation; supports partial recovery after PTS
BF844	Stabilizes mutant CLRN1N48K protein	Usher syndrome type III‐associated progressive HL	Attenuates progressive HL and prevents deafness in a mouse model
Vorinostat/SAHA	HDAC inhibition; maintains RelA/p65 K310 acetylation and promotes NF‐κB‐mediated pro‐survival gene expression	Kanamycin/furosemide‐induced ototoxic HL	Protects against cochlear hair‐cell loss and hearing‐threshold shifts
Diethylaminobenzaldehyde (DEAB)	ALDH inhibition; suppresses retinoic acid signaling and increases Pou4f3 expression	DFNA15‐associated progressive HL; Pou4f3 (Δ/+) mouse model	Preserves auditory function and outer hair‐cell survival; attenuates progressive HL
Ebselen/SPI‐1005	Glutathione peroxidase‐mimicking antioxidant and anti‐inflammatory SM	Noise‐induced and aminoglycoside‐induced cochlear injury; sensorineural HL, tinnitus, and other auditory conditions	Limits oxidative stress and inflammatory injury within the cochlea; advanced into clinical evaluation
Sodium thiosulfate	Otoprotective SM against platinum‐related cochlear toxicity	Cisplatin‐induced HL	Delayed administration after cisplatin reduces the incidence of HL in randomized pediatric trials
FX‐322	Intratympanic regenerative SM composed of CHIR99021 and valproic acid; activates cochlear progenitor‐associated regenerative pathways	Stable sensorineural HL	Developed to promote hair‐cell regeneration; phase 1b study showed tolerability and improvement in speech‐intelligibility measures in a subset
ORC‐13661	High‐affinity permeant blocker of the hair‐cell mechanotransduction channel; reduces ototoxin entry into sensory hair cells	Aminoglycoside‐ and cisplatin‐induced injury	Protects zebrafish lateral‐line hair cells, mouse cochlear cultures, and rat hearing from ototoxic injury

5. Conclusion

HL is a prevalent and disabling condition that profoundly affects the lives of millions of individuals worldwide. Understanding the underlying pathophysiology of different types of hearing impairment is essential for the development of targeted and effective therapeutic interventions. This review has provided an overview of the complex mechanisms involved in sensorineural, conductive, and mixed HL, thereby serving as a foundation for exploring innovative treatment strategies.

The emergence of therapeutic SMs offers a versatile and promising approach for addressing the challenges associated with HL. This review has discussed diverse SM‐based strategies, including pharmacological chaperones, transcriptional modulation, ion channel modulation, neuroprotective compounds, apoptosis inhibition, and regenerative approaches. These SM‐based interventions may target specific pathways and mechanisms implicated in the pathogenesis of hearing impairment, creating opportunities for more tailored therapeutic approaches. However, the clinical implementation of such mechanism‐based therapies depends on the accurate identification of the underlying pathophysiology in individual patients. At present, precise diagnosis of the cellular and molecular mechanisms responsible for human hearing impairment remains limited, except in certain well‐defined conditions such as auditory neuropathy.

Overall, this review provides a focused resource for researchers, clinicians, and stakeholders in the field of auditory therapeutics. The insights presented here may inform future research directions and support the development of innovative and targeted treatments for individuals affected by hearing impairment.

Author Contributions

Maryam Naghinejad: writing – original draft, writing – review and editing. Farzaneh Motallebi: writing – original draft. Elaheh Hasani: writing – review and editing. Moein Kohkalani: writing – review and editing. Sepideh Parvizpour: writing – review and editing. Sima Mansoori Derakhshan: writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Use of Artificial Intelligence

During the preparation of this manuscript, the authors used ChatGPT (OpenAI) solely for English language editing and improving readability.

Transparency Statement

Sepideh Parvizpour and Sima Mansoori Derakhshan affirm that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Naghinejad M., Motallebi F., Hasani E., Kohkalani M., Parvizpour S., and Mansoori Derakhshan S., “Small Molecule Therapeutic Approaches With a Greater Focus on Hearing Loss: A Review,” Health Science Reports 9 (2026): e73323. 10.1002/hsr2.73323.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.