# XIAP Stabilizes DDRGK1 to Promote ER‐Phagy and Protects Against Noise‐Induced Hearing Loss

## TL;DR

This study shows that XIAP helps protect against noise-induced hearing loss by stabilizing DDRGK1 and promoting ER-phagy in cochlear hair cells.

## Contribution

The paper identifies XIAP- and DDRGK1-mediated ER-phagy as a novel therapeutic target for noise-induced hearing loss.

## Key findings

- XIAP binds to DDRGK1, increasing its stability and activating ER-phagy.
- Gastrodin reduces noise-induced hair cell loss and hearing damage by promoting XIAP and DDRGK1.
- Noise exposure inhibits ER-phagy flux and reduces XIAP and DDRGK1 levels in cochlear cells.

## Abstract

Noise‐induced hearing loss (NIHL) is a common cause of acquired sensorineural hearing loss. Excessive endoplasmic reticulum (ER) stress‐induced apoptosis of cochlear hair cells contributes to NIHL. ER autophagy (ER‐phagy) is a critical pathway for maintaining ER homeostasis and cell survival. DDRGK1 (DDRGK domain containing 1) is a crucial receptor in ER‐phagy, essential for the removal of injured ER components. This work investigates the involvement of DDRGK1‐mediated ER‐phagy in NIHL, which has remained unclear. ER‐phagy flux is inhibited in HEI‐OC1 cells treated with hydrogen peroxide. Noise exposure reduces XIAP (X‐linked inhibitor of apoptosis protein) and DDRGK1 protein levels in these cells. Moreover, XIAP binds to DDRGK1, increasing the stability of DDRGK1 and activating ER‐phagy. Notably, in noise‐exposed CBA/CaJ mice, gastrodin, a traditional Chinese medicine ingredient, reduces noise‐induced loss of cochlear hair cells, ribbon synaptic damage, and hearing loss by promoting XIAP expression, thereby increasing DDRGK1 protein levels and activating ER‐phagy. These findings highlight XIAP‐DDRGK1‐mediated ER‐phagy as a novel therapeutic target for NIHL treatment.

Mechanism of GAS‐mediated protection against noise‐induced hearing loss (NIHL). Noise exposure activates the ATF4/eIF2α axis, downregulating XIAP and promoting DDRGK1 degradation, thereby inhibiting ER‐phagy and leading to hair cell (HC) death. GAS treatment rescues XIAP and DDRGK1 expression, reactivating ER‐phagy to mitigate HC loss, synaptic damage, and hearing impairment. Created with BioRender.com.