Endoplasmic reticulum (ER) stress is a common stress factor during the aging process. Heat shock factor 1 (HSF1) plays a critical role in ER stress; however, its exact function in age-related hearing loss (ARHL) has not been fully elucidated. The purpose of the present study was to identify the role of HSF1 in ARHL. In this study, we demonstrated that the loss of inner and outer hair cells and their supporting cells was predominant in the high-frequency region (basal turn, 32 kHz) in ARHL cochleae. In the aging cochlea, levels of the ER stress marker proteins p-eIF2α and CHOP increased as HSF1 protein levels decreased. The levels of various heat shock proteins (HSPs) also decreased, including HSP70 and HSP40, which were markedly downregulated, and the expression levels of Bax and cleaved caspase-3 apoptosis-related proteins were increased. However, HSF1 overexpression showed significant hearing protection effects in the high-frequency region (basal turn, 32 kHz) by decreasing CHOP and cleaved caspase-3 and increasing the HSP40 and HSP70 proteins. These findings were confirmed by HSF1 functional studies using an auditory cell model. Therefore, we propose that HSF1 can function as a mediator to prevent ARHL by decreasing ER stress-dependent apoptosis in the aging cochlea.

In mammals, hearing loss is irreversible due to the lack of the regenerative capacity of the auditory epithelium. However, stem/progenitor cells in mammalian cochleae may be a therapeutic target for hearing regeneration. The ubiquitin proteasome system plays an important role in cochlear development and maintenance. In this study, we investigated the role of ubiquitin C-terminal hydrolase L1 (UCHL1) in the process of the transdifferentiation of auditory supporting cells (SCs) into hair cells (HCs). The expression of UCHL1 gradually decreased as HCs developed and was restricted to inner pillar cells and third-row Deiters’ cells between P2 and P7, suggesting that UCHL1-expressing cells are similar to the cells with Lgr5-positive progenitors. UCHL1 expression was decreased even under conditions in which supernumerary HCs were generated with a γ-secretase inhibitor and Wnt agonist. Moreover, the inhibition of UCHL1 by LDN-57444 led to an increase in HC numbers. Mechanistically, LDN-57444 increased mTOR complex 1 activity and allowed SCs to transdifferentiate into HCs. The suppression of UCHL1 induces the transdifferentiation of auditory SCs and progenitors into HCs by regulating the mTOR pathway.