Targeting Phospholipid Metabolism as an Effective Hearing Protection Strategy

Huanyu Mao; Wenli Ni; Lupeng Ma; Xiang Li; Yanping Zhang; Yuzheng Zhao; Wenyan Li; Huawei Li; Yan Chen

doi:10.1007/s12264-025-01433-0

Targeting Phospholipid Metabolism as an Effective Hearing Protection Strategy

Neurosci Bull. 2025 Jun 28. doi: 10.1007/s12264-025-01433-0. Online ahead of print.

Authors

Huanyu Mao^#^{1

2}, Wenli Ni^#^{1

2}, Lupeng Ma^#³, Xiang Li^{1

2}, Yanping Zhang^{1

2}, Yuzheng Zhao⁴, Wenyan Li^{5

6

7}, Huawei Li^{8

9

10}, Yan Chen^{11

12}

Affiliations

¹ ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China.
² NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai, 200031, China.
³ Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
⁴ Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
⁵ ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China. wenyan_li@fudan.edu.cn.
⁶ NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai, 200031, China. wenyan_li@fudan.edu.cn.
⁷ The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China. wenyan_li@fudan.edu.cn.
⁸ ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China. hwli@shmu.edu.cn.
⁹ NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai, 200031, China. hwli@shmu.edu.cn.
¹⁰ The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China. hwli@shmu.edu.cn.
¹¹ ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China. chenyan0528@fudan.edu.cn.
¹² NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai, 200031, China. chenyan0528@fudan.edu.cn.

^# Contributed equally.

PMID: 40580390
DOI: 10.1007/s12264-025-01433-0

Abstract

Cochlear hair cell (HC) damage is a primary cause of sensorineural hearing loss. In this study, we performed metabolomic profiling of cochlear sensory epithelium following neomycin-induced HC injury and identified elevated arginine metabolism as a key metabolic characteristic of damaged HCs. Using a highly sensitive and specific biosensor, we confirmed that injury induced an increase in arginine levels within cochlear HCs. By manipulating the levels of arginine and its downstream metabolites, we discovered that unmetabolized arginine exerts a strong protective effect on cochlear HCs, independent of its downstream metabolites, such as nitric oxide. Furthermore, integrated metabolomic and transcriptomic analyses revealed that arginine plays a critical role in reprogramming phospholipid metabolism. Arginine supplementation enhanced membrane phospholipid saturation through the Lands cycle and de novo lipogenesis, and protected HCs from phospholipid peroxidation-induced membrane damage and subsequent cell death. Notably, arginine supplementation protected hearing from both noise- and aminoglycoside-induced injury in mice. These findings underscore the role of unmetabolized arginine in modulating phospholipid metabolism and preventing membrane damage in cochlear HCs, highlighting that targeting phospholipid metabolism is an effective hearing protection strategy.

Keywords: Hair cell; Membrane lipid bilayer; Oxidative stress; Phospholipid remodeling; Sensorineural hearing loss.