According to the World Report of Hearing published by the WHO in 2021, hearing loss currently affects more than 1.5 billion people, and 430 million people of them experience moderate or greater levels of hearing loss. Exposure to ototoxic medicines and loud noises, and age-related hearing loss are specific highlighted causative factors that can lead to hearing loss [1]. Cisplatin, a highly effective chemotherapy agent, is widely utilized in the treatment of various solid tumors [2,3]. Hearing loss affects more than 50 % of patients receiving platinum-based chemotherapy, with an annual increase of approximately 500,000 cases [4,5]. Currently, there are few FDA-approved treatments, such as sodium thiosulfate only for children, that specifically target this condition. Over the past two decades, clinical trials have been conducted to explore the potential of various repurposed drugs, as well as novel drug candidates, for mitigating cisplatin-induced hearing loss [6]. These efforts reflect the ongoing search for effective treatments to address the significant side effects of cisplatin therapy.

Previous research has established a direct link between oxidative stress, reactive oxygen species (ROS), and the cytotoxic effects of cisplatin [7]. Upon cellular uptake, cisplatin binds to major biomolecules, disrupts various organelles, and impairs the antioxidant system, leading to oxidative stress and subsequent cell death, including apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis [7]. Oxidative stress is a primary factor that underlies cisplatin-induced hearing loss, and the antioxidant system, particularly glutathione peroxidase (GPx), plays a crucial role in mitigating this damage [7]. However, GPx activity in the plasma is known to decrease progressively following cisplatin therapy [8]. Research has also shown that cisplatin induces the overexpression of chaperones, leading to lysosome-dependent degradation of GPx and subsequent terminal kidney injury [9]. Previous studies have shown that cisplatin impairs mitochondrial structure, enhances the generation of reactive oxygen species (ROS), and upregulates caspase levels, culminating in the apoptosis of hair cells [7]. Furthermore, we and other researchers have shown that cisplatin treatment elevates intracellular iron and lipid peroxide levels in HEI-OC1 cells and cochlear hair cells [[10], [11], [12], [13]]. This effect is associated with mitochondrial dysfunction and a reduction in GPx4 expression, suggesting that ferroptosis plays a role in cisplatin-induced hearing loss. Therefore, modulating GPx activity may provide a protective effect against this type of hearing loss.

GPxs catalyze the reduction of hydrogen peroxide or organic hydroperoxides, typically with glutathione (GSH) as a reductant [14]. Most members of the GPx family (GPx1, GPx2, GPx3, GPx4, and GPx6) contain a selenocysteine (Sec) residue at their active site (Fig. 1A), which is crucial for their activity [15]. Isoselenazolones have been identified as mimics of these GPxs because they structurally resemble the active site of GPxs (Fig. 1B) (for a detailed explanation, refer to the first section in the Results and Discussion section). The representative compound SPI-1005 exhibits heightened activity under severe oxidative stress conditions [16] and shows therapeutic potential for noise-induced hearing loss by oral administration in clinical trials [17]. However, the efficacy of SPI-1005 is limited; therefore, the drug has not been approved after over ten years of investigation in clinical trials. Additionally, the efficacy of SPI-1005 in treating drug-related hearing loss remains a subject of debate [18]. The possible reasons might be its relatively low GPx-like activity and extremely poor water solubility (5.0 μg/ml in water), which may limit its in vivo effectiveness. In addition, further studies are needed to determine whether isoselenazolones, as GPx mimics, can mitigate ferroptosis in the context of cisplatin-induced hair cell damage.

Quantum chemistry (QC) calculations have significantly contributed to drug discovery and design [19], including our previous successful examples [20,21]. However, the application is still limited due to the large amount of calculation. In this research, the frontier molecular orbital (FMO) theory approach was used as a convenient prediction method for the GPx-like activity of isoselenazolones. Then we discovered isoselenazolones with improved GPx-like activity and enhanced water solubility. Additionally, we assessed the efficacy of these compounds in protecting against cisplatin-induced hair cell loss in neonatal mouse cochlear explants and conducted auditory evaluations through in vivo studies. Our investigation also focused on deciphering the underlying mechanisms involved, particularly emphasizing the role of these compounds in mitigating ferroptosis. This study paves the way for the development of potential therapeutic agents to treat hearing loss and illuminates the complex cellular protective mechanisms of GPx mimics.