Rare ginsenoside Rk1 protects against cisplatin-induced auditory damage by regulating the MST1/LONP1 pathway

BACKGROUND: Cisplatin is a broad-spectrum chemotherapeutic agent; however, its dose-dependent ototoxicity limits its clinical application. Ginsenosides possess anti-inflammatory and antioxidant activities, offering potential therapeutic value for chemotherapy-induced auditory damage. PURPOSE: To investigate the protective effect of rare ginsenosides against cisplatin-induced hearing loss and to elucidate the underlying molecular mechanisms. METHODS: In vivo and in vitro models of cisplatin-induced injury were established to compare the therapeutic efficacy of primary ginsenosides (Rb1, Rg1, Re) and rare ginsenosides (Rk1, Rg5, Rh2). Auditory function in mice from different treatment groups was assessed using auditory brainstem response and otoacoustic emissions. Transcriptome sequencing combined with Western blotting was performed to investigate the molecular mechanisms underlying cisplatin-induced ototoxicity, with a focus on elucidating the regulatory role of Rk1 in the MST1/LONP1 pathway and its auditory protective effects. RESULTS: Both in vitro and in vivo studies confirmed that ginsenosides significantly attenuated cisplatin-induced cochlear hair cell damage, and the protective effect of rare ginsenosides was superior to that of primary ginsenosides. Further mechanistic investigation revealed that activation of the MST1/LONP1 pathway was involved in the pathological process of cisplatin-induced ototoxicity. We selected Rk1 as a representative rare ginsenoside and demonstrated that Rk1 could directly bind to MST1, regulate the MST1/LONP1 pathway, improve mitochondrial function, and protect against cisplatin-induced hair cell damage and hearing loss. CONCLUSION: Our study revealed the involvement of the MST1/LONP1 pathway in cisplatin-induced ototoxicity. More importantly, we elucidated that Rk1 attenuates hearing loss by regulating this pathway, providing novel scientific evidence and a potential strategy for the prevention and treatment of cisplatin-induced ototoxicity.