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<p>Cisplatin-induced ototoxicity limits its clinical utility and may adversely impact cochlear implant outcomes. This study investigated the role of the HES1/PI3K/AKT/mTOR signaling axis in cisplatin-evoked cytotoxicity in HEI-OC1 auditory cells. Our results demonstrated that cisplatin treatment significantly upregulated HMGB1/NLRP3-mediated inflammatory responses, as evidenced by increased protein levels of HMGB1 and NLRP3, along with elevated mRNA expression of TNF-α, IL-6, and IL-1β. Concurrently, cisplatin induced pronounced oxidative stress, characterized by elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, alongside reduced superoxide dismutase (SOD) activity and glutathione (GSH) content. Notably, genetic knockdown of HES1 markedly attenuated cisplatin-induced oxidative stress and inflammation. Mechanistically, cisplatin activated the PI3K/AKT/mTOR pathway, and pharmacological activation of PI3K reversed the protective effects conferred by <i>Hes1</i> knockdown. Conversely, inhibition of this pathway alleviated cisplatin-induced cytotoxicity. Rescue experiments further confirmed that HES1 exacerbates cisplatin-induced damage through activation of the PI3K/AKT/mTOR axis. Collectively, our findings identify the HES1/PI3K/AKT/mTOR signaling pathway as a critical mechanism underlying cisplatin ototoxicity, highlighting a potential therapeutic target for the prevention of sensorineural hearing loss.</p>

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Mechanistic study of HES1/PI3K/Akt/mTOR signaling pathway in cisplatin-induced sensorineural hearing loss

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月26日

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  • Yang Xiao,
  • Ce Zhang,
  • Yuewen Li,
  • Dong Su,
  • Meihua Sun,
  • Oulai Li,
  • Chuxiong Gong,
  • Xiao Zhang,
  • Jing Ma,
  • Tiesong Zhang

摘要

Cisplatin-induced ototoxicity limits its clinical utility and may adversely impact cochlear implant outcomes. This study investigated the role of the HES1/PI3K/AKT/mTOR signaling axis in cisplatin-evoked cytotoxicity in HEI-OC1 auditory cells. Our results demonstrated that cisplatin treatment significantly upregulated HMGB1/NLRP3-mediated inflammatory responses, as evidenced by increased protein levels of HMGB1 and NLRP3, along with elevated mRNA expression of TNF-α, IL-6, and IL-1β. Concurrently, cisplatin induced pronounced oxidative stress, characterized by elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, alongside reduced superoxide dismutase (SOD) activity and glutathione (GSH) content. Notably, genetic knockdown of HES1 markedly attenuated cisplatin-induced oxidative stress and inflammation. Mechanistically, cisplatin activated the PI3K/AKT/mTOR pathway, and pharmacological activation of PI3K reversed the protective effects conferred by Hes1 knockdown. Conversely, inhibition of this pathway alleviated cisplatin-induced cytotoxicity. Rescue experiments further confirmed that HES1 exacerbates cisplatin-induced damage through activation of the PI3K/AKT/mTOR axis. Collectively, our findings identify the HES1/PI3K/AKT/mTOR signaling pathway as a critical mechanism underlying cisplatin ototoxicity, highlighting a potential therapeutic target for the prevention of sensorineural hearing loss.