Abstract
The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins. However, if the unfolded protein response fails to restore endoplasmic reticulum homeostasis, it can trigger pro-inflammatory and pro-death signals, which are implicated in various malignancies and are currently being investigated for their role in retinal degenerative diseases. This paper reviews the role of the unfolded protein responsein addressing endoplasmic reticulumstress in retinal degenerative diseases. The accumulation of ubiquitylated misfolded proteins can lead to rapid destabilization of the proteome and cellular demise. Targeting endoplasmic reticulum stress to alleviate retinal pathologies involves multiple strategies, including the use of chemical chaperones such as 4-phenylbutyric acid and tauroursodeoxycholic acid, which enhance protein folding and reduce endoplasmic reticulum stress. Small molecule modulators that influence endoplasmic reticulum stress sensors, including those that increase the expression of the endoplasmic reticulum stress regulator X-box binding protein 1, are also potential therapeutic agents. Additionally, inhibitors of the RNAse activity of inositol-requiring transmembrane kinase/endoribonuclease 1, a key endoplasmic reticulum stress sensor, represent another class of drugs that could prevent the formation of toxic aggregates. The activation of nuclear receptors, such as PPAR and FXR, may also help mitigate ER stress. Furthermore, enhancing proteolysis through the induction of autophagy or the inhibition of deubiquitinating enzymes can assist in clearing misfolded proteins. Combination treatments that involve endoplasmic-reticulum-stress-targeting drugs and gene therapies are also being explored. Despite these potential therapeutic strategies, significant challenges remain in targeting endoplasmic reticulum stress for the treatment of retinal degeneration, and further research is essential to elucidate the mechanisms underlying human retinal diseases and to develop effective, well-tolerated drugs. The use of existing drugs that target inositol-requiring transmembrane kinase/endoribonuclease 1 and X-box binding protein 1 has been associated with adverse side effects, which have hindered their clinical translation. Moreover, signaling pathways downstream of endoplasmic reticulum stress sensors can contribute to therapy resistance. Addressing these limitations is crucial for developing drugs that can be effectively used in treating retinal dystrophies. In conclusion, while the unfolded protein response is a promising therapeutic target in retinal degenerative diseases, additional research and development efforts are imperative to overcome the current limitations and improve patient outcomes.