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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1430162

Investigation of METTL3 as an Inhibitor of Kanamycin-Induced Ototoxicity via Stress Granule Formation

Provisionally accepted
Yan Wu Yan Wu 1*Yu-Yu Huang Yu-Yu Huang 1*Lu-Yao Wang Lu-Yao Wang 1*Yan Yang Yan Yang 2*Fei-Lun Cui Fei-Lun Cui 3*Shu-Na Li Shu-Na Li 1*
  • 1 Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
  • 2 Liaoning Medical Device Test Institute, Shenyang, China
  • 3 Taizhou Second People's Hospital, Taizhou, China

The final, formatted version of the article will be published soon.

    Background: Methyltransferase-like 3 (METTL3), a component of the N6-methyladenosine (m6A) methyltransferase family, exhibits significant expression in HEI-OC1 cells and cochlear explants. Aminoglycoside antibiotics, known for their ototoxic potential, frequently induce irreversible auditory damage in hair cells, predominantly through oxidative stress mechanisms. However, the specific role of METTL3 in kanamycin-induced hair cell loss remains unclear. Objective: This study aims to elucidate the mechanisms by which METTL3 contributes to kanamycin-induced ototoxicity. Methods and Results: In vivo experiments demonstrated a notable reduction in METTL3 expression within cochlear explants following kanamycin administration, concomitant with the formation of stress granules (SGs). Similarly, a 24-hour kanamycin treatment led to decreased METTL3 expression and induced SG formation both in HEI-OC1 cells and neonatal cochlear explants, corroborating the in vivo observations. Lentivirus-mediated transfection was employed to overexpress and knockdown METTL3 in HEI-OC1 cells. Knockdown of METTL3 resulted in increased reactive oxygen species (ROS) levels and apoptosis induced by kanamycin, while concurrently reducing SG formation. Conversely, overexpression of METTL3 attenuated ROS generation, decreased apoptosis rates, and promoted SG formation induced by kanamycin. Therefore, METTL3-mediated SG formation presents a promising target for mitigating kanamycin-induced ROS generation and the rate of apoptosis. Conclusion: This finding indicates that METTL3-mediated SG formation holds potential in mitigating kanamycin-induced impairments in cochlear hair cells by reducing ROS formation and apoptosis rates.

    Keywords: Kanamycin, METTL3, ototoxicity, Reactive Oxygen Species, Stress granule

    Received: 11 May 2024; Accepted: 26 Jul 2024.

    Copyright: © 2024 Wu, Huang, Wang, Yang, Cui and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Yan Wu, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Yu-Yu Huang, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Lu-Yao Wang, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Yan Yang, Liaoning Medical Device Test Institute, Shenyang, China
    Fei-Lun Cui, Taizhou Second People's Hospital, Taizhou, China
    Shu-Na Li, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.