Treatment with the Ferroptosis Inhibitor Ferrostatin-1 Attenuates Noise-Induced Hearing Loss by Suppressing Ferroptosis and Apoptosis

Abstract

Hair cell death induced by excessive reactive oxygen species (ROS) has been identified as the major pathogenesis of noise-induced hearing loss (NIHL). Recent studies have demonstrated that cisplatin- and neomycin-induced ototoxicity can be alleviated by ferroptosis inhibitors. However, whether ferroptosis inhibitors have a protective effect against NIHL remains unknown. We investigated the protective effect of the ferroptosis inhibitor ferrostatin-1 (Fer-1) on NIHL in vivo in CBA/J mice and investigated the protective effect of Fer-1 on tert-butyl hydroperoxide (TBHP)-induced hair cell damage in vitro in cochlear explants and HEI-OC1 cells. We observed ROS overload and lipid peroxidation, which led to outer hair cell (OHC) apoptosis and ferroptosis, in the mouse cochlea after noise exposure. The expression level of apoptosis-inducing factor mitochondria-associated 2 (AIFM2) was substantially increased following elevation of the expression of its upstream protein P53 after noise exposure. The ferroptosis inhibitor Fer-1was demonstrated to enter the inner ear after the systemic administration. Administration of Fer-1 significantly alleviated noise-induced auditory threshold elevation and reduced the loss of OHCs, inner hair cell (IHC) ribbon synapses, and auditory nerve fibers (ANFs) caused by noise. Mechanistically, Fer-1 significantly reduced noise- and TBHP-induced lipid peroxidation and iron accumulation in hair cells, alleviating ferroptosis in cochlear cells consequently. Furthermore, Fer-1 treatment decreased the levels of TfR1, P53, and AIFM2. These results suggest that Fer-1 exerted its protective effects by scavenging of ROS and inhibition of TfR1-mediated ferroptosis and P53-AIFM2 signaling pathway-mediated apoptosis. Our findings suggest that Fer-1 is a promising drug for treating NIHL because of its ability to inhibit noise-induced hair cell apoptosis and ferroptosis, opening new avenues for the treatment of NIHL.

The Inheritance of Hearing Loss and Deafness: A Historical Perspective

“…Metal overload and epigenetic changes may also affect the cochlea or the sensorial epithelium, playing a role in various forms of sensorineural hearing loss. [77,78]. These facts were observed by the same group, describing how iron homeostasis genes predispose to one of the most difficult and complex forms of hearing loss, i.e., idiopathic sudden sensorineural hearing loss [79].…”

Intrinsic mechanism and pharmacologic treatments of noise-induced hearing loss

“…The first breakthrough comes from a recent study that showed that ferrostatin-1 (Fer-1), a well-known ferroptosis inhibitor, protects against NIHL. This shows that ferroptosis is involved 111 .…”

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

“…AIFM2 is transcriptionally activated by p53, binds to DNA in a nonsequence‐specific manner, and induces caspase‐independent apoptosis 298 . A study has also shown that AIFM2 can play an important role in the process of suppressing ferroptosis in a ubiquitin‐dependent manner 299 …”

“…298 A study has also shown that AIFM2 can play an important role in the process of suppressing ferroptosis in a ubiquitin-dependent manner. 299 Activation of p53 signaling can upregulate the expression of insulin-like growth factor-binding protein 3 (IGF-BP3), thereby promoting apoptosis. 300 IGF-BP3 is a growth hormone-dependent IGF binding protein.…”

“… 298 A study has also shown that AIFM2 can play an important role in the process of suppressing ferroptosis in a ubiquitin‐dependent manner. 299 …”