2. Academic Validation
  3. STM2457 decreases m6A methylation to reduce cisplatin-induced ototoxicity via MAPK signaling

STM2457 decreases m6A methylation to reduce cisplatin-induced ototoxicity via MAPK signaling

  • Biochem Pharmacol. 2025 May:235:116820. doi: 10.1016/j.bcp.2025.116820.
Jiahao Liao 1,  Xingxing Wu 1,  Qingdong Zeng 2,  Qin Huo 1,  Guohui Nie 3
Affiliations

Affiliations

  • 1 Department of Otolaryngology, Shenzhen Institute of Translational Medicine, Shenzhen Key Laboratory of Nanozymes and Translational Cancer Research, Medical Innovation Technology Transformation Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China; School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China.
  • 2 Department of Otolaryngology, Shenzhen Institute of Translational Medicine, Shenzhen Key Laboratory of Nanozymes and Translational Cancer Research, Medical Innovation Technology Transformation Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China.
  • 3 Department of Otolaryngology, Shenzhen Institute of Translational Medicine, Shenzhen Key Laboratory of Nanozymes and Translational Cancer Research, Medical Innovation Technology Transformation Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China. Electronic address: nieguohui@email.szu.edu.cn.
PMID: 39983847 DOI: 10.1016/j.bcp.2025.116820
Abstract

Cisplatin, a chemotherapeutic drug used to treat cancerous solid tumors, can result in ototoxicity due to serious toxic side effects resulting in irreversible hearing loss. Here, we investigated the effects of N6-methyladenosine (m6A) methylation on cisplatin-induced ototoxicity by using in vitro cochlear explants as a model system to explore the effect of the Methyltransferase-like 3 (METTL3) inhibitor STM2457 in ameliorating cisplatin-induced ototoxicity. STM2457 pretreatment was shown to significantly reduce Reactive Oxygen Species (ROS) accumulation and the loss of hair cells (HCs) in different regions of the organ of Corti. STM2457 pretreatment led to significant reductions in TUNEL labeling, signifying a reduction in Apoptosis. Additionally, expression of the apoptosis-related protein Bax was significantly decreased, while the ratio of Bcl-xL was markedly increased. Transcriptomic measurements of the STM2457 + cisplatin group revealed significant enrichment of the Mitogen-Activated Protein Kinases (MAPK) signaling pathway, which when stimulated, could block the protective effect of STM2457 in cisplatin-treated HCs. Thus, we describe a mechanism by which STM2457 decreases cisplatin-related HC death in cochlear explants in vitro through activation of the MAPK pathway. This study reports for the first time that reducing RNA m6A methylation might protects against cisplatin-induced ototoxicity. Our data indicate that STM2457 can serve as an effect anti-apoptotic drug to decrease ototoxicity caused by cisplatin-induced ROS accumulation, effectively preventing cisplatin-induced hair cells loss.

Keywords

Cisplatin; MAPK; Ototoxicity; STM2457; m6A.

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