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

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.