Cisplatin-Induced APE2 Overexpression Disrupts MYH9 Function and Causes Hearing Loss.

Abstract

Cisplatin remains a cornerstone chemotherapy for many solid tumors but is limited by dose-limiting toxicities, including nephrotoxicity, peripheral neuropathy, and ototoxicity-the latter of which disproportionately affects pediatric patients and lacks effective prevention strategies. Although therapeutic approaches to mitigate cisplatin-induced toxicity are urgently needed, the underlying mechanisms driving organ-specific injury remain incompletely understood. We previously identified apurinic/apyrimidinic endonuclease (APE) 2 as a critical mediator of cisplatin-induced acute kidney injury through disruption of mitochondrial integrity. In this study, we extend these findings to cisplatin-induced hearing loss (C-HL). We demonstrate that cisplatin selectively induces APE2, but not APE1, overexpression in murine and human outer hair cells. Using an inducible, outer hair cell-specific APE2 transgenic mouse model, we show that APE2 overexpression alone is sufficient to cause high-frequency hearing loss, accompanied by hair cell loss and stereocilia disorganization visualized by electron microscopy. Mechanistically, we identified a direct interaction between APE2 and MYH9, mapped the critical MYH9-binding domains, and demonstrated that APE2 knockdown preserved mitochondrial metabolism and protected cochlear cells from cisplatin-induced apoptosis. Notably, APE2 depletion activated an ATR-p53 signaling axis, promoting nuclear p53 localization and suppressing mitochondrial apoptotic pathways. Together, these findings reveal a noncanonical, APE2-dependent mechanism driving C-HL and suggest that targeting APE2 may offer a novel therapeutic strategy to prevent cisplatin-induced ototoxicity.

Significance: These results reveal an unexpected role of APE2 via its interaction with MYH9, emphasizing the therapeutic promise of targeting APE2 for preventing C-HL in patients with cancer.