Autophagy-dependent ferroptosis contributes to cisplatin-induced hearing loss

Jian, Bingquan; Pang, Jiaqi; Xiong, Hao; Zhang, Weijian; Zhan, Ting; Su, Zhi; Lin, Hanqing; Zhang, Huasong; He, Wuhui; Zheng, Yiqing

doi:10.1016/j.toxlet.2021.07.010

Cited by 31 publications

(19 citation statements)

References 64 publications

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“…The latest research has indicated that autophagydependent ferroptosis contributes to the ototoxicity induced by cisplatin. In this study, autophagic flux was blocked by chloroquine, attenuating cisplatin injury (Jian et al, 2021). Ferroptosis is a ROS-and iron-dependent cell death.…”

Section: Autophagy In House Ear Institute-organ Of Corti 1 Cellsmentioning

confidence: 61%

Cellular autophagy, the compelling roles in hearing function and dysfunction

Wan

Zhang

Hua

2022

Front. Cell. Neurosci.

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Sensorineural hearing loss (SNHL) is currently a major health issue. As one of the most common neurodegenerative diseases, SNHL is associated with the degradation of hair cells (HCs), spiral ganglion neurons (SGNs), the stria vascularis, supporting cells and central auditory system cells. Autophagy is a highly integrated cellular system that eliminates impaired components and replenishes energy to benefit cellular homeostasis. Etiological links between autophagy alterations and neurodegenerative diseases, such as SNHL, have been established. The hearing pathway is complex and depends on the comprehensive functions of many types of tissues and cells in auditory system. In this review, we discuss the roles of autophagy in promoting and inhibiting hearing, paying particular attention to specific cells in the auditory system, as discerned through research. Hence, our review provides enlightening ideas for the role of autophagy in hearing development and impairment.

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Section: Autophagy In House Ear Institute-organ Of Corti 1 Cellsmentioning

confidence: 61%

Cellular autophagy, the compelling roles in hearing function and dysfunction

Wan

Zhang

Hua

2022

Front. Cell. Neurosci.

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“…Cisplatin-induced hair cell death via ferroptosis has been reported in several early studies [ 23 , 29 , 43 ]. We chose to detect the process of lipid peroxidation, a hallmark alteration of ferroptosis, in which MDA and 4-HNE, as products of lipid peroxidation, can be used to detect the occurrence of ferroptosis [ 21 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…It was officially included as one of the regulated cell death types by the cell death nomenclature committee in 2018 [ 18 ]. The results of our preliminary experiments suggest that ferroptosis is one of the important molecular mechanisms of cisplatin-induced hearing loss [ 23 ]. In cellular experiments, HEI-OC1 cell lines treated with cisplatin showed significantly higher levels of lipid peroxide and a significant decrease in cell survival [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…The results of our preliminary experiments suggest that ferroptosis is one of the important molecular mechanisms of cisplatin-induced hearing loss [ 23 ]. In cellular experiments, HEI-OC1 cell lines treated with cisplatin showed significantly higher levels of lipid peroxide and a significant decrease in cell survival [ 23 ]. However, the specific mechanism of ferroptosis in the occurrence and development of cisplatin ototoxicity still needs further in-depth study.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of ACSL4-Catalyzed Lipid Peroxidation Process Resists Cisplatin Ototoxicity

Huang

Wei

et al. 2022

Oxidative Medicine and Cellular Longevity

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Cisplatin-induced ototoxicity is one of the common side effects during its treatment and there are no effective measures to prevent it. Our study aimed to investigate the effect of ACSL4-catalyzed lipid peroxidation on cisplatin-induced hearing loss and its possible protective mechanisms. We used a variety of cisplatin ototoxicity models, including HEI-OC1 cell line, cochlear explants, and ET4 GFP+ zebrafish. After measuring the experimental concentrations of cisplatin by CCK8 assay and immunofluorescence, respectively, we examined the levels of lipid peroxidation by MDA content, 4-HNE content, and C11-BODIPY (581/591) probe. Then, we used two ferroptosis inhibitors, FER-1, and Vit-E to protect hair cells. We found that cisplatin significantly increased the levels of lipid peroxidation and that this process can be resisted by the ferroptosis inhibitors. Afterwards, we performed metabolomic assays on the cisplatin-treated hair cells. The metabolite levels were significantly altered in the experimental group compared to the control group, and the highest degree of change was observed in the glutathione metabolic pathway and the arachidonic acid metabolic pathway. Therefore, we screened the key enzymes on the arachidonic acid metabolic pathway in the hair cells after cisplatin treatment and found that ACSL4 had the greatest regulatory value. Further, we reduced the level of lipid peroxide in hair cells by specifically inhibiting the expression of ACSL4, which protected hair cells from cisplatin damage at source. In conclusion, the lipid peroxidation process regulated by ACSL4 may be an important factor contributing to the sensitivity of hair cells to cisplatin. Inhibition of ACSL4 expression may be an effective preventive measure against cisplatin ototoxicity.

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“…A specific inhibitor of ferroptosis, ferrostatin-1 was shown to diminish cell death due to cisplatin in HEI-OC1 cells and in mouse cochlear explants by improving mitochondrial function [ 30 , 31 ]. Blockade of autophagy using chloroquine was found to ameliorate ferroptosis induced by cisplatin in HEI-O C1 cells, suggesting that the cell death induced by ferroptosis was associated with upregulation of autophagy [ 33 ]. However, targeting ferroptosis to prevent cisplatin induced hearing loss could be problematic, since ferroptosis is one of the mechanisms that underlie cisplatin induced killing of tumor cells [ 34 ].…”

Section: Oxidative Stressmentioning

confidence: 99%

Oxidative Stress and Inflammation Caused by Cisplatin Ototoxicity

et al. 2021

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Hearing loss is a significant health problem that can result from a variety of exogenous insults that generate oxidative stress and inflammation. This can produce cellular damage and impairment of hearing. Radiation damage, ageing, damage produced by cochlear implantation, acoustic trauma and ototoxic drug exposure can all generate reactive oxygen species in the inner ear with loss of sensory cells and hearing loss. Cisplatin ototoxicity is one of the major causes of hearing loss in children and adults. This review will address cisplatin ototoxicity. It includes discussion of the mechanisms associated with cisplatin-induced hearing loss including uptake pathways for cisplatin entry, oxidative stress due to overpowering antioxidant defense mechanisms, and the recently described toxic pathways that are activated by cisplatin, including necroptosis and ferroptosis. The cochlea contains G-protein coupled receptors that can be activated to provide protection. These include adenosine A1 receptors, cannabinoid 2 receptors (CB2) and the Sphingosine 1-Phosphate Receptor 2 (S1PR2). A variety of heat shock proteins (HSPs) can be up-regulated in the cochlea. The use of exosomes offers a novel method of delivery of HSPs to provide protection. A reversible MET channel blocker that can be administered orally may block cisplatin uptake into the cochlear cells. Several protective agents in preclinical studies have been shown to not interfere with cisplatin efficacy. Statins have shown efficacy in reducing cisplatin ototoxicity without compromising patient response to treatment. Additional clinical trials could provide exciting findings in the prevention of cisplatin ototoxicity.

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Autophagy-dependent ferroptosis contributes to cisplatin-induced hearing loss

Cited by 31 publications

References 64 publications

Cellular autophagy, the compelling roles in hearing function and dysfunction

Cellular autophagy, the compelling roles in hearing function and dysfunction

Regulation of ACSL4-Catalyzed Lipid Peroxidation Process Resists Cisplatin Ototoxicity

Oxidative Stress and Inflammation Caused by Cisplatin Ototoxicity

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