Age-related hearing loss (ARHL), commonly referred to presbycusis, manifests as bilateral symmetric sensorineural hearing impairment resulting from the senescence of the auditory system (De Iorio et al., 2019; Li et al., 2023). Population-based researches suggest that the significant hearing loss (defined as an average of pure-tone thresholds between 0.5–4.0 kHz exceeding 25 dB HL) among individuals aged from 60 to 80 years ranges from 21% to 27% (Jafari et al., 2019; Löhler et al., 2019). ARHL exerts detrimental effects on physical and mental health, cognitive function (Uchida et al., 2019), dementia (Chern and Golub, 2019), social interaction, depression, and the overall quality of life among the elderly. Notably, slight degrees of hearing impairment can heighten the long-term susceptibility of dementia and cognitive Beclin. Presently, the treatment options available for ARHL patients are reliant on aural rehabilitation services, specifically the use of hearing aids or cochlear implants, which aim to facilitate auditory plasticity and localization (Jafari et al., 2019). Regrettably, our comprehension of ARHL remains considerably limited. There are currently no specific pharmaceuticals or therapies that demonstrate a curative effect on ARHL. Drug-based interventions can, at best, only serve to prevent or alleviate mild to moderate hearing impairment (Bowl and Dawson, 2019). In order to advance innovative therapeutic approaches, we found it imperative to establish a thorough comprehension of the fundamental molecular mechanisms governing ARHL.

Autophagy involves in the preservation of hair cell morphology and functionality, which closely associates with ARHL (Fujimoto et al., 2017; Xiong et al., 2022). Serving as a pivotal intracellular degradation pathway (Wu et al., 2020), autophagy encompasses the encapsulation and transport of compromised organelles and abnormally large molecules to lysosomes for degradation. In the autophagy-related researches, microRNAs (miRNAs) emerge as significant contributors (Huang et al., 2021; Li et al., 2022; Qian et al., 2021). MiRNAs are endogenous, short, noncoding RNA molecules recognized for their role in regulating gene expression by engaging in target mRNA's 3′-untranslated region (3′-UTR) sequence-specific base pairing. Moreover, miRNAs expressions exhibit a strong correlation with the severity of hearing loss (Lee et al., 2018) and other age-related disease (Lan et al., 2019; Zhang et al., 2020). For example, the study by Pang et al (Pang et al., 2017) elucidated the role of miR-34a, which targets ATG9A, in governing autophagy flux and its implication in initiating ARHL. Similarly, Li et al (Li et al., 2022) discovered that miR-489, acting as a negative regulator of NDP52, suppresses autophagy and mitigates neomycin-induced damage to hair cells. Additionally, Xiong et al (Xiong et al., 2019) unveiled the fact, that miR-34a/SIRT1 exerts protective effect on defending cochlear hair cells against oxidative stress by stimulating mitochondrial autophagy. This mechanism contributes to the postponement of ARHL onset. However, the question, whether miR-130 regulates autophagy and contributes to the pathogenesis of ARHL remains an area that requires further elucidation.

Among the miRNAs known to modulate autophagy, miR-130b-3p has been associated with the modulation of peroxisome proliferator-activated receptor gamma (PPARγ/PPARG). Research conducted by Wu et al (Wu et al., 2022) has provided evidence that miR-130b-3p orchestrates autophagic process and is involved in the degeneration of intervertebral discs. Currently, insufficient solid evidence confirming presence of a direct interaction between PPARγ and ARHL. However, the role of PPARγ as a regulator of autophagy suggests a potential avenue for investigation. In light of the information presented, it is plausible that miR-130b-3p potentially participate in the regulation of hearing loss through its modulation of PPARγ, which functions as an autophagy regulator.

Sensory ARHL is characterized by the degeneration of both outer and inner hair cells within the cochlea. This degeneration typically initiates at the basal end of the cochlea and gradually advances towards the apex. Basal atrophy primarily underlies the high-frequency hearing loss that is typically associated with sensory ARHL (Slade et al., 2020). Consequently, for our in vitro experiments, we opted to work with a hair cell line. HEI-OC1 is among the limited number of mouse auditory cell lines that are utilized for research endeavors. These cells express the Prestin protein, a pivotal motor protein found in the outer hair cells of the cochlea. This unique characteristic renders HEI-OC1 cells invaluable for gaining insights into novel functionalities and underlying mechanisms related to this critical auditory protein. Moreover, among the various mammalian model organisms used in aging research, the mouse is recognized for its robustness and reliability. Mice have a relatively short lifespan, which allows for the accelerated manifestation of age-related effects. Given these considerations, we established our in vivo model using C57BL/6J mice, a specific strain known for its progressive decline in auditory function as it ages (Bowl and Dawson, 2019; Zhang et al., 2021). Concurrently, our in vitro research utilizes HEI-OC1 cells, providing a complementary approach to investigate the mechanisms underlying age-related hearing loss.

In the initial phase of our research (Zhang et al., 2019), we embarked on a multifaceted approach. This involved conducting differential gene screening, constructing protein interaction networks, predicting target genes, and carrying out functional enrichment analyses using microarray datasets. Through these endeavors, we discerned a potential association between miR-130b and the development of presbyopia, with miR-130b seemingly targeting PPARγ. However, the precise molecular mechanisms underlying this relationship remained elusive. TargetScan analysis further supported the notion that miR-130b-3p had the capacity to target PPARγ. Given well-established role of oxidative stress as a key contributor in ARHL, we sought to replicate the aging cochlear microenvironment in vitro by introducing exogenous H2O2 to HEI-OC1 cells. Subsequently, we embarked on a comprehensive investigation. We designed the C57BL/6J mouse model featuring miR-130b-3p knockout and PPARγ overexpression. We induced oxidative stress within HEI-OC1 using H2O2 and simultaneously manipulated miR-130b-3p level and PPARγ externally. Our main goal was the investigation of the involvement of miR-130b-3p/PPARγ in ARHL, and to elucidate the potential mechanisms that underlie this phenomenon.