NIHL is a very prominent type of SNHL that is particularly pronounced among adults. Two different conditions must be separated: acute acoustic trauma caused by, e.g., blast exposure and hearing loss as a consequence of chronic noise exposure.

In this review, we focus on NIHL resulting from ongoing noise trauma. It is the result of ongoing high levels of occupational, military, and recreational noise, which are the most common triggers (Wang et al., 2020; Zhou and Zhang, 2024).

Specifically, young people are at risk of developing NIHL because of the increasing use of headphones to enjoy music (Imam and Hannan, 2017; Jiao et al., 2022).

Individuals exposed to sound levels exceeding 85 dB for more than 5 h per week are at risk of experiencing permanent hearing damage over time. Notably, the relationship between occupational noise-induced hearing loss and the associated risk of various adverse health outcomes varies with frequency, among other factors (Imam and Hannan, 2017; Jiao et al., 2022).

Taken together, the World Health Organization reports that loud sound exposure potentially causes NIHL in more than 600 million people worldwide (Chadha et al., 2021; Alberti et al., 1979).

This paper provides an overview of NIHL, focusing on its pathophysiology; its impact on membrane transporters, ion channels, and BLB structures; and associated symptoms, comorbidities, and emerging therapeutic approaches. Recent advancements in neuromodulation and vector-based strategies show great promise in overcoming biological barriers such as BLB, facilitating the development of innovative treatment options. The primary aim of this review is to examine NIHL in detail and explore its underlying mechanisms, physiological effects, and cutting-edge therapeutic strategies for its effective management and prevention.

TTS is defined as at least 10 dB of threshold elevation at one or more frequencies between 2 and 4 kHz. This threshold shift may reach 50 dB (Liberman, 2016). TTS lasts from minutes to days, depending on the pathophysiology of the damage. Low-level TTS is mediated by ion channels that are activated by extracellular ATP (Housley et al., 2013). The relevant ATP receptor P2RX2 is a nonselective cation channel expressed in cochlear hair cells (HCs) and epithelial cells lining the scala media. Noise stimulates local ATP release in the cochlea, and ATP opens the channels, which then shunts the endocochlear current away from the HC transduction channel (Morton-Jones et al., 2015; Thorne et al., 2004). Higher levels of TTS (up to 50 dB) are due to additional mechanisms, such as uncoupling of the outer HC stereocilia from the tectorial membrane (Nordmann et al., 2000) and swelling of the afferent endings underneath the inner HCs, suggestive of excitotoxicity due to the release of excessive glutamate from overstimulated HCs (Puel et al., 1998). Other evidence suggests that damaging levels of noise lead to metabolic overstimulation and subsequent generation of free radical species (Henderson et al., 2006; Shi and Nuttall, 2003) like reactive oxygen species (ROS) and reactive nitrogen species (RNS).

When exposed to sufficiently loud and long-lasting noise, the ability of the cochlea to recover becomes overwhelmed, leading to irreversible hearing loss. This type of hearing loss is mainly linked to damage to and loss of cochlear HCs, but damage to neurons and other parts of the cochlea can also contribute to PTS (Kurabi et al., 2017). This damage can directly disrupt stereocilia (Slepecky, 1986), which diminishes or completely stops their function. In severe cases, damage can even affect the overall structure of the sensory part of the cochlea, disrupting HCs and their support cells. This type of damage can also create a connection between two fluid-filled areas in the cochlea, endolymph, and perilymph, allowing excessive levels of potassium to reach the basal poles of remaining intact HCs, leading to their death. However, damaging levels of noise begin well below the threshold of such frank mechanical damage. The majority of NIHL is caused by damage to HCs through biochemical processes that occur within the cells themselves via ROS production, as in the case of TTS.

In the cochlea, noise exposure generates excessive ROS and RNS, leading to oxidative stress, lipid peroxidation, and DNA damage, which trigger apoptosis in hair cells and disrupt the BLB (Yamashita et al., 2005; Le Prell et al., 2007; Mao and Chen, 2021; Natarajan et al., 2024). These molecules also induce inflammation, exacerbating cochlear damage (Mao and Chen, 2021; Natarajan et al., 2024). At a systemic level, ROS and RNS contribute to endothelial dysfunction, sympathetic nervous system activation, and renin–angiotensin–aldosterone system (RAAS) activation, all of which increase vascular resistance and promote hypertension (Yamashita et al., 2005). The interaction between oxidative stress in the cochlea and systemic vascular dysfunction suggests a potential mechanistic link between NIHL and hypertension. This connection provides insights for therapeutic interventions aimed at targeting oxidative pathways (Yamashita et al., 2005; Le Prell et al., 2007).

The cascade of events initiated by ROS induction entails lipid peroxidation within the cochlea, thereby giving rise to the generation of highly noxious metabolic byproducts. While the products of lipid peroxidation alone can induce apoptosis, lipid peroxidation byproducts possessing vasoactive properties, such as isoprostanes, may contribute to a diminished blood supply to the cochlea (Ohinata et al., 2000; Thorne et al., 1987; Seidman et al., 1999). Noise-induced ischemia and subsequent reperfusion might further potentiate the generation of ROS in a positive feedback loop (Kurabi et al., 2017). Furthermore, ROS-mediated mechanisms involve the induction of inflammatory responses, including the production of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), which themselves have the ability to damage the cochlear structure and function (Tan et al., 2016).

The strial BLB is a highly specialized network of capillaries that tightly controls the permeability of the capillaries and controls macromolecular exchange between the blood and the interstitial space in the cochlea (Forster et al., 2022; Forster et al., 2005). The strial BLB thus maintains cochlear homeostasis and protects the cochlea from blood-borne potentially ototoxic endobiotics and xenobiotics.

The strial BLB is fundamentally similar to the blood–brain barrier (BBB), which separates brain interstitial fluid from blood (Figure 1). The BLB separates the inner ear fluid compartments (perilymph and endolymph) from capillaries of the vasculature and is composed of vascular endothelial cells coupled together by tight junctions. BLB is critical for maintaining ionic homeostasis in inner ear fluid and preventing the entry of deleterious substances into the inner ear. Recent studies have implicated the loss of integrity of the BLB in several inner ear pathologies, including acoustic trauma, infection, ototoxin-induced hearing loss, and age-related hearing loss (presbycusis).

In this context, loud sounds affect almost all cochlear cell types and induce inflammation and drug-induced cochleotoxicity (Li et al., 2011; Vethanayagam et al., 2016). Acoustic trauma (Suzuki et al., 2002) involves several external and intrinsic factors that can profoundly modulate the permeability of the BLB (Taylor et al., 2008), increasing its permeability and subsequent uptake of drugs indirectly by inducing inflammation and degeneration of sensory cells and auditory neurons (Figure 3).

Different disease states comorbid with NIHL can alter BLB physiology and increase its permeability through inflammation and oxidative stress: cochlear inflammation (Kastenbauer et al., 2001; Hirose et al., 2014) caused by acoustic trauma, in turn, contributes to the degeneration of cochlear sensory cells.

Computational modeling and simulation of drug permeation through biological barriers is a promising approach for developing novel drug therapies for pathological processes such as NIHL. By providing insights into drug behavior, barrier characteristics, and physiological conditions, in silico modeling can aid in the design of more effective and targeted drug delivery strategies across the BLB.

Recent advancements in computational modeling and simulation techniques have enabled researchers to better understand the underlying mechanisms of drug transport and identify potential therapeutic targets and drug transporters at barrier interfaces, such as BBB-ChT (blood–brain barrier choline transporter) and P-gp (P-glycoprotein) (Shityakov and Forster, 2013; Shityakov and Forster, 2014a,b). However, most simulation models have been developed for the BBB, which separates the brain and blood compartments.

On the other hand, the complex nature of the auditory system and the BLB has posed significant challenges for traditional drug discovery methods, as there are limited experimental data available to develop novel approaches such as structure–activity–property relationship (QSAR and QSPR) models. The BLB is a specialized structure that separates the inner ear from the systemic circulation and is composed of tightly packed endothelial cells that restrict the diffusion of molecules and ions across the barrier. This presents a significant challenge for drug delivery through the blood into the perilymph of the inner ear, where traditional systemic drug administration is ineffective (Le and Blakley, 2017). Owing to this, permeation partitioning coefficients, such as the logBB (blood–brain partitioning coefficient) and logPS (permeability–surface area product), are still needed for the BLB (logBL–blood–labyrinth partitioning coefficient) to develop accurate regression models already implemented for the BBB (Shityakov and Forster, 2013; Shityakov et al., 2013; Shityakov et al., 2021b; Shityakov et al., 2016). To address these limitations, a publicly accessible experimental logBL database is needed to provide the quantitative data required for developing accurate BLB permeability prediction models. In the future, such datasets may become available through dedicated biomedical consortia or specialized ADME/Tox platforms that prioritize inner ear–focused research.

SNHL is a broad term used to describe various disorders that affect the functioning of the cochlea, the part of the inner ear that is dedicated to hearing. These disorders can result from genetic mutations, environmental factors, or age-related degeneration. Some of the most common types of peripheral auditory pathology include NIHL, ARHL, and ototoxicity. Indeed, many drugs that could theoretically cross the BLB have ototoxic side effects, which can exacerbate hearing loss rather than treat it. Various drugs often trigger oxidative stress, disrupt ion homeostasis, or induce direct cytotoxicity in cochlear hair cells, ultimately leading to irreversible hearing impairment (Lin et al., 2021).

Therefore, drug-induced ototoxicity can be evaluated via machine learning (ML) and deep learning (DL) models, similar to the consensus model, which is based on individual ML/DL, with total accuracies of 0.95 and 0.90, respectively (Huang et al., 2021).

An example of possible computational modeling is the oxidative stress at the BLB as a main factor of NIHL and ARHL, which is mediated via the Keap1-NRF2 pathway (Li et al., 2021; Oishi et al., 2020). In the context of this pathway, protein–protein molecular docking and molecular dynamics simulations can be used to understand the intermolecular affinity and conformational changes that occur in proteins. Keap1 is a substrate adaptor protein that binds to NRF2 and targets it for degradation. However, when a cell is exposed to oxidative stress, NRF2 is released from Keap1 and translocates to the nucleus, where it activates genes that protect against oxidative stress followed by hearing loss (Henderson et al., 2006).

The delivery of the gene encoding vesicular glutamate transporter 3 (VGLUT3) via AAV1 has been demonstrated to restore hearing function in mice lacking this protein (Akil et al., 2012). VGLUT3 is expressed in cochlear inner hair cells and holds promise as a potential vehicle for drug delivery across the BLB (Zhang et al., 2020).

For example, a drug could be designed to bind to VGLUT3, allowing it to be transported into the cochlea, where it could exert its therapeutic effects. By using VGLUT3 as a targeted delivery mechanism, drugs can be targeted to the inner ear, minimizing systemic exposure and reducing potential side effects. This approach could be useful for treating conditions such as NIHL, where direct delivery to the cochlea is challenging because of the restrictive nature of the BLB.

Hypothetically, the incorporation of glutamic acid as a moiety into the active pharmaceutical ingredient (API) could yield a prodrug form that enhances its permeation across the BLB via the glutamate–aspartate transporter. This transporter, which is highly expressed in the cochlea and plays a critical role in maintaining glutamate concentrations in the perilymph at nontoxic levels during acoustic overstimulation, could also facilitate drug permeation across the BLB. Importantly, the prodrug, which is initially pharmacologically inactive, undergoes metabolic conversion at the site of action, releasing the active drug. This targeted approach could not only improve the therapeutic efficacy of drugs intended for inner ear conditions but also minimize potential systemic side effects by limiting the exposure of nontarget tissues to the active drug.

As a result, computational methods such as molecular docking, molecular dynamics simulations, QSAR/QSPR analysis, transporter-enhanced BLB permeability prediction, high-throughput screening, and network pharmacology are essential but still need to be developed to provide novel therapies for SNHL. These cutting-edge methods can help identify potential drug candidates, predict their activity, optimize their properties, and analyze complex interactions between drugs, target molecules, and biological pathways.

The hypothesis that NIHL may lead to dampening of the vagus nerve implies that stimulation of the nerve may have a positive effect on NIHL. Therefore, an emerging therapeutic option could be to use vagus nerve stimulation (VNS) to treat NIHL. VNS is increasingly being used to treat conditions such as epilepsy, depression, and chronic inflammation, as well as an aid to rehabilitation and as a technique for cognitive improvement (Stefan et al., 2012; Ventureyra, 2000). Nonetheless, VNS requires implantation of a device via an invasive technique, which may not be acceptable for many patients (Zafeiropoulos et al., 2023). These limitations led to the development of transcutaneous VNS (tVNS) by stimulating the auricular branch of the vagus nerve at the tragus or the concha of the ear (Stavrakis et al., 2024; Hanna et al., 2021; Stavrakis et al., 2020; Tran et al., 2019). This technique is associated with minimal risk, thus opening up the possibility for novel applications even in healthy individuals (Figure 6).

taVNS in combination with tone therapy has been demonstrated to be an efficient and safe method that does not have significant side effects. Several preclinical and small cohort clinical studies support this assumption to combine taVNS with tones to improve auditory processing, e.g., in patients with tinnitus or possibly NIHL (Kochilas et al., 2020; Yakunina et al., 2018; Raj-Koziak et al., 2023; Suk et al., 2018).

With respect to acquired hearing loss following noise trauma, one could refer to reports in animals showing that VNS paired with specific tones improved tinnitus during follow-up and was sufficient to reverse the abnormal plasticity of the primary auditory cortex shown to be associated with tinnitus (Engineer et al., 2011). On the other hand, pilot clinical studies highlight the feasibility and safety of VNS paired with tones in patients with moderate to severe chronic tinnitus (Tyler et al., 2017). These studies combined with reported beneficial effects on hypertension (Annoni et al., 2015; Chapleau et al., 2016; Annoni et al., 2019; Nagai et al., 2023) and heart failure (Tran et al., 2019; Stavrakis et al., 2022), with minimal, if any, side effects, provide sufficient evidence that studies on this topic should be extended and moved forward.

Notably, noninvasive vagus nerve stimulation reduces BBB disruption in a rat model of ischemic stroke (Yang et al., 2018) such that a transferable effect to the strial BLB following NIHL can be assumed. VNS is known to reduce inflammation and oxidative stress, which are key factors in both BBB and BLB disruption. Given the functional similarities between the BBB and BLB, it is reasonable to hypothesize that VNS could protect the BLB in NIHL. However, direct experimental evidence is needed to confirm this effect, as the current assumption is based on indirect findings from stroke models. Further research is needed to validate the potential protective role of VNS in preserving BLB integrity in NIHL.