Matrix metalloproteinases proteolyze RAB proteins and contribute to cisplatin-induced ototoxicity

Authors

Bhavsar, A. P., Zandi, Z., Hartley, B., Bassiouni, W., DuVal, M. G., Luo, S., Spavor, M. J., Allison, W. T., Julien, O., Schulz, R.

Abstract

Matrix metalloproteinases (MMPs) are rapidly expressed and activated in response to oxidative stress and contribute to various pathological conditions. Cisplatin is a highly effective chemotherapeutic agent; however, its clinical use is limited by its associated permanent hearing loss (ototoxicity). While cisplatin-induced oxidative stress and inner ear cell death are well-established, the contribution of MMPs remains unclear. In this study, we demonstrate that cisplatin exposure triggers activation of MMP-2 and MMP-9 and expression of an intracellular N-terminal-truncated isoform of MMP-2 in mouse inner ear hair cells. Pharmacological inhibition of MMP-2 and genetic knockdown of Mmp-9 enhanced hair cell survival and attenuated cisplatin-induced inflammation and cytotoxicity. Furthermore, proteomic analysis revealed that proteins involved in intracellular trafficking, including RAB proteins, may serve as potential substrates of intracellular MMP-2 upon cisplatin exposure, pointing to a previously unrecognized mechanism of cisplatin-induced hair cell injury. In vitro analysis confirmed that MMP-2 cleaves RAB9A in response to cisplatin, and in silico analyses predicted MMP-2-preferred cleavage sites on RAB9A. Collectively, our findings identify MMP-2 as a promising therapeutic target for mitigating cisplatin-induced ototoxicity.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 04 Mar 2026.

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