2. Academic Validation
  3. Isoliquiritigenin attenuates cisplatin-induced hearing loss and ototoxicity by activating the Keap1-Nrf2-ARE pathway

Isoliquiritigenin attenuates cisplatin-induced hearing loss and ototoxicity by activating the Keap1-Nrf2-ARE pathway

  • Free Radic Biol Med. 2025 Oct 3:241:599-616. doi: 10.1016/j.freeradbiomed.2025.10.004.
Ying Chen 1,  Xiaoyang Luo 2,  Yanyan Deng 3,  Guanghao Zhu 3,  Xiayan Chu 3,  Jingjing Zhu 4,  Siyi Shao 4,  Lijun Zhang 3,  Xiang Chen 5,  Yuqing Chen 2,  Chang Lin 6,  Guangbo Ge 7,  Shuhui Wu 8
Affiliations

Affiliations

  • 1 Department of Otolaryngology, Shanghai Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine, Baoshan Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201999, China; State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 2 Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otolaryngology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
  • 3 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 4 Department of Otolaryngology, Shanghai Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine, Baoshan Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201999, China.
  • 5 Department of Thyroid Surgery, Shanghai Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine, Baoshan Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201999, China.
  • 6 Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otolaryngology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China. Electronic address: linc301@sina.com.
  • 7 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: geguangbo@shutcm.edu.cn.
  • 8 Department of Otolaryngology, Shanghai Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine, Baoshan Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201999, China. Electronic address: wsh-1227@163.com.
PMID: 41046947 DOI: 10.1016/j.freeradbiomed.2025.10.004
Abstract

Cisplatin-induced hearing loss (CIHL), a major dose-limiting toxicity of cisplatin, is primarily caused by oxidative stress and Apoptosis in cochlear hair cells. This study aims to investigate the otoprotective effects of Isoliquiritigenin (ISL, a natural Nrf2 agonist) on CIHL and to elucidate the underlying anti-CIHL mechanism(s) of ISL. Initially, ISL was identified as a natural Nrf2 agonist from a phytochemical library using a luciferase reporter gene system. The otoprotective effects of ISL were then investigated in HEI-OC1 cells, cochlear explants, and in cisplatin-induced ototoxicity murine models. In cisplatin-induced ototoxicity mice, ISL markedly restored full-frequency auditory brainstem response (ABR) thresholds and attenuated cisplatin-induced hair cell loss in the cochlea. In HEI-OC1 cells and cochlear explants, ISL significantly attenuated cisplatin-triggered Reactive Oxygen Species (ROS) overproduction, mitochondrial dysfunction, and hair cell Apoptosis. Mechanistically, ISL covalently modify two critical cysteine residues (Cys226 and Cys288) of KEAP1, which subsequently stabilized Nrf2 and upregulated the expression of downstream antioxidant proteins including NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1) and superoxide Dismutase (SOD). Collectively, our findings clearly demonstrate that ISL significantly attenuates cisplatin-induced hearing loss (CIHL) by activating the Keap1-Nrf2-ARE signaling via covalent modifying two key cysteine residues on KEAP1.

Keywords

Cisplatin-induced ototoxicity (CIO); Hearing loss; Isoliquiritigenin (ISL); Keap1/Nrf2 signaling; Oxidative stress.

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