Role of RGS17 in Cisplatin-induced Cochlear Inflammation and Ototoxicity Via Caspase-3 Activation

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2025 Mar 10

PMID 40061942

Authors

Raheem F H Al Aameri

Entkhab M A Alanisi

Dheyaa Al Sallami

Ian Alberts

Shelley Tischkau

Leonard P Rybak

Vickram Ramkumar

Affiliations

Soon will be listed here.

Abstract

Cisplatin is a chemotherapy drug used to treat different solid tumors, including ovarian, bladder, lung, and head and neck cancers. One of its significant side effects is ototoxicity, especially when high doses are required. Cisplatin-induced ototoxicity is associated with increased cochlear cell death resulting from DNA damage, caspase activation, oxidative stress, inflammation, and glutamate excitotoxicity. The regulator of G protein signaling 17 (RGS17), a member of the RGS-RZ subfamily, hastens the hydrolysis of GTP to GDP on the G subunit. In the current study, we demonstrate the role of in cisplatin-induced cochlear inflammation and ototoxicity. C57BL/6J mice treated with two cycles of cisplatin (3.5 mg/kg) showed a significant elevation in ABR thresholds, along with loss of outer hair cells and inner hair cells synapse. Furthermore, immunohistochemical analysis revealed that cisplatin administration upregulates CXCL1, accompanied by an increase in the number of CD45 and CD68-positive immune cells. On the other hand, knockout in hair cells protects against cisplatin-induced elevation of ABR thresholds, outer hair cell loss, cochlear inflammation, and inner hair cell synaptopathy. Moreover, knockout downregulates CXCL1 immunolabeling and decreases the number of CD45 and CD68-positive immune cells induced by cisplatin. These results suggest that is implicated in cisplatin ototoxicity, potentially by initiating the immune cascade, and indicate as a relevant target for treating cisplatin ototoxicity.

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