A Non-Linear Ototoxic Response to Cisplatin Is Associated with Autophagy and PTEN/PI3K/AKT Signaling in Cochlear Hair Cells and Spiral Ganglion Neurons

Background: Cisplatin-induced ototoxicity is generally considered dose-dependent. However, cellular adaptive responses under severe cisplatin stress remain incompletely understood. This study aimed to investigate the non-linear ototoxic response to cisplatin and explore the potential involvement of autophagy in the survival of cochlear hair cells and spiral ganglion neurons. Methods: Cochlear explants from postnatal day 3 rats and HEI-OC1 cells were treated with different concentrations of cisplatin (0–400 μM). HCs and SGNs injury and apoptosis were assessed by immunofluorescence staining, hair cell counting, TUNEL assays, cell viability assays, and Western blotting. PCR arrays were used to characterize neurotransmission- and autophagy-related gene expression, and transmission electron microscopy was performed to examine autophagic structures. Western blotting was further used to evaluate autophagy-related proteins and PTEN/PI3K/AKT signaling. Results: Cisplatin induced a non-linear ototoxic response in cochlear explants. Hair cell loss increased from approximately 70% at 10 μM to over 90% at 100 μM, but was markedly reduced at 400 μM. This reduced injury was accompanied by decreased apoptosis, increased LC3-II, decreased P62, and altered PTEN/PI3K/AKT signaling. In contrast, HEI-OC1 cells showed progressively reduced viability with increasing cisplatin concentration, suggesting a model-dependent response. Conclusions: High-concentration cisplatin was associated with reduced cochlear injury and enhanced autophagy-related activity in cochlear explants. These findings suggest that autophagy and PTEN/PI3K/AKT signaling are associated with the non-linear response to severe cisplatin stress.