Sphingolipid Metabolic Dysregulation Drives Cisplatin-Induced Ototoxicity Through Mitochondrial Dysfunction and Intrinsic Apoptosis.

Abstract

Cisplatin is a widely used chemotherapeutic agent, but its clinical application is limited by irreversible sensorineural hearing loss. Sphingolipid metabolism is increasingly implicated in sensory hair cell (HC) survival, yet its role in cisplatin-induced ototoxicity remains unclear. Here, we investigated the involvement of sphingolipid dysregulation in cisplatin ototoxicity and evaluated the otoprotective effects and mechanisms of fingolimod (FTY720), an FDA-approved sphingosine-1-phosphate (S1P) receptor modulator. Multiple S1P pathway modulators protected cochlear HCs from cisplatin-induced injury in vitro, supporting the involvement of S1P signaling. FTY720 preserved auditory function and reduced HC, ribbon synapse, and spiral ganglion neuron loss in acute and chronic mouse models of cisplatin-induced hearing loss. Multi-omics and molecular analyses revealed that FTY720 restored cisplatin-induced sphingolipid metabolic dysregulation and activated PI3K/AKT signaling. FTY720 consequently alleviated mitochondrial dysfunction and mitochondria-dependent intrinsic apoptosis. Importantly, FTY720 did not attenuate cisplatin-induced cytotoxicity or suppress its antiproliferative effects in cancer cells, as confirmed by viability, Calcein AM/propidium iodide (PI) double staining, and Ki67 analysis. Collectively, these findings reveal a sphingolipid metabolism-PI3K/AKT-mitochondrial apoptosis axis in cisplatin-induced ototoxicity and support FTY720 as a potential otoprotective strategy without compromising cisplatin-mediated tumor cell killing.