Inhibition of KDM5A attenuates cisplatin-induced hearing loss via regulation of the MAPK/AKT pathway

Abstract

The study aimed to investigate the potential role of lysine-specific demethylase 5A (KDM5A) in cisplatin-induced ototoxicity. The effect of the KDM5A inhibitor CPI-455 was assessed by apoptosis assay, immunofluorescence, flow cytometry, seahorse respirometry assay, and auditory brainstem response test. RNA sequencing, qRT-PCR, and CUT&Tag assays were used to explore the mechanism underlying CPI-455-induced protection. Our results demonstrated that the expression of KDM5A was increased in cisplatin-injured cochlear hair cells compared with controls. CPI-455 treatment markedly declined KDM5A and elevated H3K4 trimethylation levels in cisplatin-injured cochlear hair cells. Moreover, CPI-455 effectively prevented the death of hair cells and spiral ganglion neurons and increased the number of ribbon synapses in a cisplatin-induced ototoxicity mouse model both in vitro and in vivo. In HEI-OC1 cells, KDM5A knockdown reduced reactive oxygen species accumulation and improved mitochondrial membrane potential and oxidative phosphorylation under cisplatin-induced stress. Mechanistically, through transcriptomics and epigenomics analyses, a set of apoptosis-related genes, including Sos1, Sos2, and Map3k3, were regulated by CPI-455. Altogether, our findings indicate that inhibition of KDM5A may represent an effective epigenetic therapeutic target for preventing cisplatin-induced hearing loss.

Cocktail regimen in treatment of sudden sensorineural hearing loss

“…However, the lower rates of improvement in Grades 4 and 5, at 37.5% and 33% respectively, raise concerns about the efficacy of the treatment in patients with more severe initial hearing loss. Liu C et al( 2022) 14 & Khoza-Shangase K et al(2022) 15 also found varying degrees of treatment response based on initial hearing loss severity, suggesting that early intervention is crucial.…”

Small RNA Deep Sequencing Uncovers microRNAs Associated with Hearing Loss in Vestibular Schwannoma

“…34 A growing number of evidence suggest an important role of MAPK signaling in ototoxic drug-induced hearing loss. 35,36 Another emerging hypothesis for hearing loss mechanism in VS patients is the immune system response 37 They identified several proteins associated with increased immune response, including Ig chain and complement components, which correlated with hearing loss. Interestingly, at least two miRNAs-miR-21 and miR-7 that were overexpressed in tumor samples from PH group in our material, are associated with immune response regulation.…”

Comprehensive Transcriptomic Profiling of m6A Modification in Age-Related Hearing Loss

“…Previous evidence has shown that the MAPK signalling pathway plays an important role in regulating cell proliferation, apoptosis, autophagy, and differentiation [34], and the activated MAPK signalling pathway can promote the senescence of various cells and tissues [35,36]. However, inhibition of the MAPK signalling pathway has been confirmed to alleviate noise or drug-induced hair cell apoptosis and hearing loss [37,38], suggesting that ARHL might also be related to alteration of the MAPK signalling pathway. In addition, our results revealed that the genes with hypermethylated m6A-modified peaks were mainly enriched in RNA degradation.…”