Unveiling the HSP90 inhibitor mediated effects on endoplasmic reticulum stress and redox signaling:from a cancer inhibitor to retinal degeneration catalyst.

Retinal degeneration (RD) is a class of polygenic blind eye disease characterized by photoreceptors loss and dysfunction of retinal pigment epithelium. Thus far, there is no effective treatment to save the declining vision in RD patients. Animal models are highly precious tools for studying the pathological mechanisms of RD, and for screening potential therapeutics. AUY922 is a heat shock protein 90 inhibitor that exhibits potent anti-cancer effects. However, it causes adverse ocular reactions such as reduced visual acuity and night blindness. This study intends to explore the pathological mechanism underlying the AUY922 induced RD. In vitro study, AUY922 induced cytotoxic effects on the 661W cells, which are ascribed to endoplasmic reticulum (ER) stress and oxidative damages. ER stress inhibitor 4-PBA alleviated 661W cells apoptosis and oxidative stress. Subsequently, AUY922 was delivered into the vitreous cavity of mouse and induced selective photoreceptor death and visual impairments. Overactivation of neuroglial and retinal remodeling occurred during the degenerative process. Moreover, enhanced CHOP expression was tied to profound disturbances in redox homeostasis, which readied photoreceptors for apoptosis. The underlying mechanism should be attributed to the activation of the PERK-eIF2α-ATF4-CHOP pathway. AUY922 can compensate for the high toxicity and instability of traditional inducers in RD modeling. These results not only enrich our understanding of the toxicology of AUY922 but also provide clues for establishing reliable RD models.