Targeting Phospholipid Metabolism as an Effective Hearing Protection Strategy.

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.