The human visual system is one of the most crucial sensory systems. Deterioration in the quality of vision can have a markedly negative impact on human being, including quality of life, an increase in the number of people with disabilities, the occurrence of accidents, social isolation, and psychological well-being [1]. Visual impairment and loss have become a rapidly growing public health concern across the world. As of 2019, at least 2.2 billion people suffer from visual impairment, and at least 1 billion of them have untreated or preventable visual impairment. Among these 1 billion people, the main diseases that cause distance vision impairment or blindness include cataracts, ametropia, age-related macular degeneration (AMD), glaucoma and diabetic retinopathy (DR), and the number is expected to rise [2]. Several of the diseases are retinal degeneration (RD). RD is a group of chronic blinding diseases characterised by the progressive death of nerve cells such as photoreceptor cells, retinal ganglion cells (RGCs) and (or) retinal pigment epithelial cells (RPE). As the disease progresses, vision deteriorates due to retinal cell death and impaired retinal integrity, eventually lead to complete loss of vision [3]. Depending on the pathogenesis, RD can be divided into two categories: inherited retinal degenerative diseases (IRDs) and complex retinal degeneration. Common types of RD include AMD, DR, retinitis pigmentosa (RP) and Stargardt disease (STGD) [4]. RD is one of the major blinding diseases in the world, and the treatment of RD is also the focus of blindness prevention at this stage. As a result, a lot of research has been done on the pathogenesis and treatment of this disease.

There are many factors that contribute to the development of RD. Aging, oxidative stress, protein aggregation and inflammation are crucial factors in the occurrence of AMD [5]; hyperglycemia, inflammatory and oxidative stress are significant pathogenetic mechanisms in DR [6]. Due to the complexity of the causative factors, there are many unanswered questions about the pathogenesis and treatment of such diseases. It has been found that there are two main reasons for the occurrence of progressive apoptosis in RD. On one hand, genetic mutations cause impaired normal retinal function and retinal cell death [7, 8]. On the other hand, acquired factors can disturb the retinal microenvironment, disrupt the balance of retinal proteins and promote dysfunction and cell death of retinal neurons [9, 10, 11]. Ubiquitination is a process in which ubiquitin binds to a substrate under the co-mediation of enzymes by ubiquitin-activating enzyme (E1), ubiquitin-transferring enzyme (E2) and ubiquitin ligase enzyme (E3). It plays an important role in maintaining the environmental homeostasis and normal function of the retina. Thus when mutations in the genes or environmental factors affect the process of ubiquitination, it may lead to RD. Meanwhile, the protein degradation system plays an important regulatory role in maintaining retinal protein homeostasis [12]. There are two protein degradation systems: the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system (ALPS) (Fig. 1). The UPS is a system that selectively degrades proteins by ubiquitination modification of the substrate, while the ALPS utilizes lysosome to degrade cellular components in a process called autophagy [13]. In recent years, a growing number of studies have discussed the role of ubiquitination as well as protein degradation systems in RD, but there is a lack of overviews of the most recent research in this area.

This article comprehensively reviews recent research progress on ubiquitin-related genes, proteins and protein homeostasis in the pathogenesis of RD, and summarizes the potential targeted therapy strategies for it. The aim is to guide future studies on the role of ubiquitination in RD and its potential application in future treatments. We hope that it will contribute to enhance understanding of RD and facilitate the development of more efficient treatments.

AMD is a progressive retinal disease that affects the macula and the RPE layer beneath it. It is one of the most common causes of irreversible loss of central vision in the elderly. AMD can be classified into two distinct types according to its clinical manifestations: dry AMD, characterized by macular atrophy, and wet AMD, distinguished by neovascularization, exudation, and hemorrhaging. AMD is affected by a combination of multiple risk factors such as age, obesity, hypertension, excessive light exposure, and smoking. In the pathophysiology of AMD, RPE degradation, oxidative stress, and inflammation are considered to be important pathogenic mechanisms of AMD [29]. These mechanisms are intricately linked to retinal ubiquitination and the maintenance of protein homeostasis [30]. Therefore, it is crucial to explore the role of ubiquitination and protein degradation system in the progression and treatment of AMD.

A comprehensive association analysis of over 3000 neovascular AMD cases and more than 8000 controls from an East Asian cohort in a study by Huang et al. [31] revealed that a missense single nucleotide variant (SNV), rs7739323, which is located in the ubiquitin protein ligase E3D (UBE3D) gene is significantly associated with the development of neovascular AMD. This suggested that UBE3D, a ubiquitination-related genes, may be involved in the pathogenesis of neovascular AMD. Xia et al. [32] further verified the role of UBE3D in the mechanism of neovascular AMD through in vivo and in vitro studies. In zebrafish in vivo experiments, the UBE3D gene was knocked out. Subsequent observations revealed that the eyes of UBE3D morphants exhibited abnormal eye development, an increased number of pigment granule deposits and heightened angiogenesis. In the in vitro experiments, lentiviral gene transfer technology was used to overexpress or knockdown UBE3D expression in hRPE cells. They observed that the UBE3D-up group exhibited enhanced cell proliferation and migration following oxidative damage stimulation, whereas the converse effect was observed in the UBE3D-down group. Simultaneously, their experiments showed that UBE3D was negatively correlated with Cyclin B1, a pivotal modulator of the cell cycle in mitosis. Furthermore, the researchers found that UBE3D and autophagy may act in concert to mitigate oxidative damage while low expression of UBE3D exacerbates oxidative damage and inflammatory responses. Tao et al. [33] also validated the aforementioned research findings. The study observed abnormal accumulation of melanosomes, melanofuscin and lipofuscin, atrophy of photoreceptors, ALPS dysfunction, reduced antioxidant processes, and cell cycle dysregulation in the RPE of UBE3D knockout mice, all of which are associated with cellular senescence. Xu et al. [34] investigated the genetic susceptibility factor UBE3D-v379m SNV in relation to AMD and found that UBE3D is recruited to the double-strand break (DSB) site through a proliferating cell nuclear antigen (PCNA)-interacting protein (PIP) box and binds the Krüppel-associated box domain domain-associated protein 1 (KAP1) via R377R378, thereby mediating the homologous recombination process in heterochromatin regions. The oxidation of individuals carrying the V379M SNV leads to the segregation of UBE3D from KAP1, which impairs the DSB repair process. These findings imply that UBE3D may serve as a pivotal factor in the pathogenesis of AMD, impacting retinal development, oxidative stress, DNA damage repair and autophagy while playing a crucial role in retinal aging and neurodegeneration. Furthermore, these studies suggest that UBE3D deficiency exerts multiple effects on retinal homeostasis and propose that polymorphisms in ubiquitin-related genes may influence retinal susceptibility to age.

In another study, Xing et al. [35] identified differentially expressed genes in RPE from AMD samples and healthy controls by downloading two datasets, GSE99248 and GSE125564, from the Gene Expression Omnibus (GEO) database. The researchers examined the human retinal pigment epithelial cell line ARPE-19 in AMD samples and found that five (PSMD4, PSMD8, PSMA4, PSMB5, and PSMB6) of the top 10 key genes in cellular expression levels were linked to proteasome function. This suggested that proteasome-mediated degradation may be significantly involved in AMD. The expression levels of PSMD4, PSMD8 and PSMA4 were upregulated in ARPE-19 cells from AMD samples compared to those from healthy samples. The PSMD4-encoded protein, proteasome 26S subunit non-ATPase 4, recruits the phosphorylated and ubiquitinated NF-kappa-B inhibitor alpha (IkB$\alpha$) to the proteasome, resulting in Nuclear factor kappa-B (NF-$\kappa$B) activation and induces cell senescence. And PSMD8 is a subunit of the 19S proteasome regulatory complex. PSMD4 and PSMD8 may interact with Hsp90 to regulate the degradation of misfolded proteins in AMD. The implication is that there may be a potential correlation between the expression level of ubiquitination-related genes and the age-related degradation of RPE cells. In addition, the role of the PSMB5 and PSMB6 genes in AMD progression cannot be excluded.

The above studies demonstrated the influence of ubiquitination and protein degradation systems on AMD from a genetic perspective and reveal the potential correlation between ubiquitination, proteostasis, and AMD mechanism. The regulation of ubiquitination-related genes and proteins impacts the homeostasis of retinal proteins, and conversely, the maintenance of protein homeostasis influences the ubiquitination process, collectively contributing to the pathophysiological progression of AMD.

Based on these studies, ubiquitination modification and protein degradation systems are seen as potential targets for AMD therapy. Li et al. [36] discovered that Smurf1 (Smad ubiquitylation regulatory factor-1, a C2-WW-HECT structural domain E3 ubiquitin ligase) is upregulated in retinal injury and degeneration. It was not only involved in epithelial-mesenchymal transition (EMT) and inflammatory responses, but also established a potential link between the transforming growth factor-$\beta$ (TGF-$\beta$) and NF-$\kappa$B pathways. Injection of Smurf1 inhibitor A01 into the vitreous cavity of mice mitigated partial retinal damage caused by reactive oxygen species (ROS) and inflammatory responses, as well as inhibited EMT. This implies that inhibition of Smurf1 is a potential therapeutic target for dry AMD. Maintaining proteostasis by activating autophagy in retinal RPE cells may also serve as a therapeutic approach for AMD. Hellinen et al. [37] demonstrated that the inhibition of prolyl oligopeptase (PREP), a cytoplasmic serine protease, can induce autophagy in RPE cells, effectively reducing protein aggregation and preserving the normal structure and function of the retina. Adaptation is a universal feature of sensory systems. In rod photoreceptors, light-dependent transducin translocation and Ca${}^{2+}$ homeostasis are involved in light/dark adaptation and prevention of cells damage by light. The Cul3-Klhl18 ubiquitin ligase regulates the translocation of this protein in photosensitive cells, and its localization is controlled by the ubiquitination of uncoordinated 119 protein (Unc119). Inactivation of the ligase prevents light-induced damage to the photoreceptor [38]. This provides a new idea for the treatment of dry AMD.

In conclusion, the dysfunction of ubiquitination and protein degradation systems has multiple impacts on the pathogenesis of AMD. The ubiquitin-related gene UBE3D plays a crucial role in maintaining retinal function and homeostasis. Furthermore, genes PSMD4, PSMD8, and PSMA4, which are associated with proteasome function, have been demonstrated to be strongly correlated with AMD. The current study indicates that inhibition of the E3 ligase Smurf1 can attenuate the inflammatory response, ROS production, and EMT during the progression of AMD. Conversely, activation of autophagy helps sustain the structure and function of the retina, thereby slowing down the advancement of AMD.

DR, a common complication of diabetes, is the primary cause of vision impairment in adults aged 20 to 79. It is estimated that 415 million people aged 20 to 79 had diabetes in 2015 and this number is expected to increase to 642 million by 2040 due to the increasing prevalence of diabetes, an ageing population and longer life expectancy for people with diabetes [39]. According to the severity of the lesion, DR is classified as non-proliferative DR (NPDR) and proliferative DR (PDR). The main fundus manifestations of NPDR are microaneurysms, hemorrhages and exudates. Neovascularization, vitreous proliferation, macular oedema and even retinal detachment are the principal fundus manifestations of PDR. Hyperglycaemic (HG)-induced retinal vascular damage is the major factor contributing to DR. Other factors that contribute to the development of DR include inflammatory response, oxidative stress, apoptosis, and neoangiogenesis.

Ubiquitination is intricately linked to the pathogenic mechanisms outlined previously. The ovarian-tumor-domain-containing deubiquitinases (OTUDs) are members of the DUBs that can reverse protein ubiquitination. Zhou et al. [40] reported that a novel and rare OTUD3 c.863G$>$A (rs78466831) mutation is associated with diabetes in humans. The mutation reduced protein stability and DUB activity. Furthermore, they identified the cAMP-response element binding protein (CREB)-binding protein-dependent OTUD3 (CBP-OTUD3) signalling pathway as playing a key role in glucose and fatty acid metabolism. In light of these findings, the study by Liu et al. [41] sought to compare the laboratory characteristics of rs78466831 Type 2 Diabetes Mellitus (T2DM) patients with those of wild-type T2DM. The results demonstrated that the majority of laboratory indices, glycosylated hemoglobin (HBA1c), fasting blood glucose (FBG), oral glucose tolerance test (OGTT), C peptide (CP), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglyceride (TG), and low density lipoprotein cholesterol (LDL-C), showed no statistically significant differences between the two groups. Nevertheless, the prevalence of DR was significantly higher in the variant group than in the wild-type group, indicating that variant OTUD3 may be a biological risk factor for DR.

The aforementioned studies have examined the correlation between ubiquitination and DR at the genetic level. In addition, many studies have explored the relationship between ubiquitination-, deubiquitination-related enzymes, and the development of DR at the protein level. Hu et al. [42] reported ubiquitin-specific peptidase 25 (USP25), a DUBs, as an inflammatory regulator involved in the progression of DR. The researchers found that ubiquitination related proteins were significantly elevated in DR Tissues compared to normal tissues, with the greatest difference in USP25 expression. In the HG environment, USP25 promotes microglia activation by participating in Rho-associated coiled-coil-containing protein kinase (ROCK) to regulate NF-$\kappa$B expression and promote phosphatase NF-$\kappa$B nuclear translocation. Glial cell activation is an important event in the pathogenesis of DR, which promotes the secretion of inflammatory factors and disrupts retinal homeostasis [43]. Thus, USP25 becomes a key determinant of microglial inflammatory activation. Xu et al. [44] demonstrated that the E3 ubiquitin ligase tripartite motif-containing 40 (TRIM40) is also involved in the progression of DR by influencing the inflammatory response. The study employed a murine model of DR induced by streptozotocin (STZ). The results demonstrated that under HG-conditions, the expression of TRIM40 was down-regulated, which increased Disabled1 (DAB1, an effector protein associated with cellular events and retinal development) and promoted inflammatory responses. Another E3 ubiquitin ligase, neural precursor cell expressed developmentally downregulated 4 (NEDD4L), has also been demonstrated to be involved in DR by regulating the NF-$\kappa$B signalling pathway. A study by Cui and Ma [45] found that the expression of NEDD4L was upregulated in a mouse model in HG-environments and promotes I$\kappa$B$\alpha$ ubiquitination via I$\kappa$B kinase $\beta$ (IKK-2)-dependent, thereby enhancing inflammation, oxidative stress, and permeability of the retinal vascular endothelium and facilitating the progression of DR. USP48 of the USPs family was an important regulator of NF-$\kappa$B activity in the retina. Reduction in its expression resulted in an increase of intracellular p65 levels, subsequently amplifying tumor necrosis factor-alpha (TNF-$\alpha$)-induced NF-$\kappa$B activity and ultimately leading to photoreceptor degeneration [46]. Ubiquitination/deubiquitination-related enzymes have been identified as contributors to the progression of DR by influencing iron accumulation in retinal cells. The downregulation of USP48 in response to HG-treatment has been demonstrated to induce oxidative stress and ferroptosis in ARPE-19 cells [47]. Zhang et al. [48] found that TRIM46 (a member of the TRIM family of E3 ubiquitin ligases located on chromosome 1q21) increases the ubiquitination and degradation of glutathione peroxidase 4 (GPX4), thereby promoting HG-induced ferroptosis and inhibiting cell proliferation in human retinal capillary endothelial cells (HRCECs).

Furthermore, the disruption of retinal proteostasis is closely associated with DR. HG disrupt the autophagy pathway in retinal cells, resulting in cells apoptosis, vascular endothelial cell damage and neovascularisation [49]. Recently, more efforts have delved deeper into the potential mechanisms of autophagy in DR, leading to the identification of new therapeutic targets for the treatment of DR.

Feng et al. [50] reported that, under HG-conditions, the upregulation of high mobility group box 1 (HMGB1) in RPE cells led to increased lysosomal membrane permeability (LMP) through a cathepsin B (CTSB)-dependent pathway, ultimately resulting in dysfunction in the ALPS. Liu et al. [51] also found that in early DR, the vitreous humour secreted large amounts of the neurodegenerative factor Glial cell maturation factor-$\beta$ (GMFB) protein, which translocates the ATPase H+ Transporting V1 Subunit A (ATP6V1A) to lysosomes. This inhibits their assembly and alkalinises the lysosomes in RPE cells, resulting in abnormal ALPS and the accumulation of proteins catalysing the production of toxic lipids. These studies show that HG disrupts autophagy and promotes DR through pathways mediated by HMGB1 and GMFB.

Tight glycaemic control remains the primary treatment strategy for DR. Retinal laser photocoagulation and anti- vascular endothelial growth factor (VEGF) drugs have significantly reduced the incidence of severe vision loss in DR. However, these interventions are still ineffective in preventing the onset of DR in patients with diabetes. Therefore, there is an urgent necessity to research new pharmaceuticals for the treatment of DR.

Trotta et al. [52] discovered that $\beta$-hydroxybutyrate (BHB), a protective agent in DR, is capable of restoring retinal brain-derived neurotrophic factor (BDNF) levels and inhibiting its downstream pathways, such as the formation of autolysosomes and the activation of microglia, thus reducing inflammatory response. Notoginsenoside R1 (NGR1) is a novel saponin extracted from Panax notoginseng that has pharmacological effects for treating diabetic encephalopathy and improving microcirculatory disorders. Recent studies have shown that NGR1 can reduce oxidative stress, inflammation, and apoptosis in the retinas via by enhancing phosphatase and tensin homolog-induced kinase 1 (PINK1)-dependent mitophagy [53]. Additionally, adiponectin has been found to inhibit autophagy and retinal angiogenesis through activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signal pathway [54].

In conclusion, numerous ubiquitination-related genes and proteins have been linked to the development of DR, yet there are still many unknowns in the current research landscape. E3 ligases TRIM40 and NEDD4L, as well as DUBs family USP25 and USP48, have been identified to participate in the progression of DR by promoting retinal inflammatory response. E3 ligase TRIM46 and DUBs family USP48 are involved in the progression of DR by promoting ferroptosis in retinal cells. Furthermore, HG environment can disrupt autophagy and promote DR through HMGB1 and GMFB-mediated pathways. It is hoped that regulating autophagy through multiple pathways will lead to the discovery of drugs for DR. For instance, BHB inhibits abnormal cellular autophagy by up-regulating BDNF, NGR1 activates PINK1-dependent mitochondrial autophagy to prevented DR, and adiponectin inhibits angiogenesis caused by autophagy by regulating the PI3K/AKT/mTOR signal pathway. There are still many possibilities for the development of DR therapeutics.

IRDs are a group of rare eye diseases caused by genetic defects that result in progressive retinal degeneration and irreversible visual impairment, affecting approximately 1:2000 people worldwide [55]. The most common of these IRDs is RP, others include Stargardt disease (STGD), Leber hereditary optic neuropathy (LHON), Leber congenital amaurosis (LCA), cone or cone-rod dystrophy (CORD) and X-chromosome-associated cone dystrophy (COD), etc. IRDs are one of the most genetically heterogeneous groups of human diseases. More than 270 related genes have been identified, and research into gene therapy treatments for IRDs is active [7]. However, ubiquitination has been found to be important in the pathogenesis and treatment of some IRDs.

The study by Toulis et al. [56] investigated the potential relevance of the DUB gene USP45 to retinal function. Following the knockout of USP45 in a zebrafish model, their observations indicated that USP45 may be essential for vertebrate retinal development and suggested that genes encoding enzymes of the ubiquitin pathway may be promising candidates for causing IRDs. USP48 may be involved in the regulation and stabilisation of ciliary proteins that are key to photoreceptor function, the regulation of intracellular protein transport, and the transport of cilia to the outer segments of photoreceptors. The impairment of the cilium in retinopathy can give rise to a spectrum of pathologies, including RP, LCA, and CORD, collectively designated as retinal ciliopathies, which constitute approximately a quarter of IRDs [57, 58]. The study of Sánchez-Bellver et al. [59] identified USP48 as a potential new gene candidate for retinal ciliopathies. Furthermore, a ubiquitin-binding gene, DNA topoisomerase 1 Binding Arginine/Serine Rich Protein (TOPORS), is closely related to the normal function of photoreceptor ciliary proteins and centrosomes. Mutations in TOPORS have been identified as a cause of autosomal-dominant RP [60].

Current pharmacological treatments for RD can delay disease progression and improve vision to some extent, but their therapeutic effects are still quite limited. Ubiquitination is an important protein labelling mechanism, and ubiquitination-related genes/proteins not only affect the normal development and function of the retina, but also affect the occurrence of retinal diseases. The protein degradation pathway plays an extremely significant role in regulating the number and activity of retinal proteins, protein-protein interactions and subcellular localisation of proteins. Currently, targeted ubiquitin-related gene/protein therapy has become a focus of development. However, the study of ubiquitination-based drugs remains a relatively unexplored area in the treatment of RD. This review provides a comprehensive analysis of ubiquitin-related genes in RD (Table 2, Ref. [31, 40, 41, 42, 44, 45, 46, 47, 48, 59, 60, 63, 64, 65, 74]) and discusses potential therapeutic strategies for these diseases.

UPS is widely distributed in cells and its ubiquitination modification has recently emerged as an interesting target for drug therapy. Proteasome inhibitors such as bortezomib (VELCADE) and carfilzomib (KYPROLIS) have been used in the treatment of multiple myeloma [79, 80, 81]. In addition, bendamustine is an E3 ligase inhibitor that targets the E3 ligase linear ubiquitin assembly complex (LUBAC) and has been approved by the U.S. Food and Drug Administration for the treatment of chronic lymphocytic leukaemia, multiple myeloma, non-Hodgkin’s lymphoma, ovarian cancer and other diseases [82]. Although these proteasome inhibitors are mainly used in oncological therapy, no efficacy has been reported in ophthalmology. However, the ubiquitination degradation mechanism has been applied to the treatment of RD. For example, research shows that injecting Smurf1 inhibitor A01 into the vitreous cavity of mice can reverse some of the retinal damage caused by ROS and inflammatory responses, thus slowing the progression of AMD [36].

Several natural plant and drug products are now known to promote UPS function and autophagy, thereby alleviating environment-related retinal damage. For instance, polyphenol quercetin, a natural substance found in fruits and vegetables, has been shown to enhance retinal cell degradation and self-renewal by inhibiting mTOR [83]. NGR1, extracted from Panax notoginseng, has been shown to inhibit inflammatory response and neovascularisation through pink1-dependent enhancement of mitophagy [53]. Both curcumin and nanocurcumin were found to increase proteasome activity in RPE cells in a study by Ramos de Carvalho et al. [84], with nanocurcumin showing less cytotoxic effects. Fung et al. [85] found that the antioxidant luteolin inhibited autophagosome formation, reducing oxidative stress, inflammation and apoptosis in retinal cells. All of these pharmacological studies are designed to minimize retinal cell death and maintain the homeostasis of the retinal environment, with nutritional support serving as a prerequisite for therapeutic success.

Due to the complexity of the proteins involved in the protein degradation system, drugs targeting this system have historically lacked selectivity. Additionally, toxicity, resistance, and efficacy issues of certain drugs have posed challenges, further hindering the development of proteasomal inhibitors. De Cesare et al. [86] have carried out a high-throughput, label-free screening of ubiquitin E2 enzymes and E3 ligases based on Matrix-Assisted Laser Desorption/Ionization Time of Flight (MALDI-TOF) mass spectrometry. This method is a versatile tool for drug discovery in the ubiquitin pathway, which can detect the ubiquitin transfer activity of E2 enzymes and E3 ligases, identifiy E2/E3 active pairs, assess the potency and specificity of inhibitors, and screen compound libraries in vitro without the need for chemical or fluorescent probes. It also reduces the risk of false positives and negatives by using non-physiological E2/E3 ligase substrates. Researchers are shifting from the traditional occupancy-driven approach of enzyme inhibitors to a mechanism that targets event-driven processes. This is achieved through proteolysis targeting chimera (PROTAC) and molecular glue technology, which provides highly selective control of targeting inhibition. PROTACs are small heterobifunctional molecules that consist of a module that binds to the target protein and a module that recruits the E3 ligase. Molecular glue is a low molecular weight molecule that binds to a specific protein and adds the desired interaction partner, such as E3 ligase, to its interactome. This creates a new binding surface on the protein, providing greater specificity, activity and duration of action than conventional occupancy-based small-molecule inhibitors [87, 88]. To broaden the range of potential substrates, several types of PROTACs are also under development, including autophagy-targeted chimeric (AUTACs) [89], lysosome-targeted chimeric (LYTACs) [90] and several PROTACs that have been used to treat breast and prostate cancer by targeting the estrogen and androgen receptors respectively [91]. However, PROTACs are not currently being used to treat RD. It is a feasible concept to develop highly selective PROTACs or molecular glues to regulate retinal cell death.

This review summarizes the involvement of ubiquitination and protein degradation systems in RDs and suggests potential therapeutic strategies for these diseases. However, there are still many uncharted areas regarding the role of ubiquitination modifications in the pathogenesis of RD. Appropriate stimulation of the protein degradation system may help maintain retinal cell homeostasis, but excessive ubiquitination may accelerate disease progression. The next research goal is the identification of targeted ubiquitination regulators for specific retinal diseases and the validation of cellular and animal assays to evaluate their therapeutic potential. The aim of this review is to provide a basis for future research in this area.

All authors JW, XC, YX and YG contributed significantly to searching the literature and writing the original manuscript. JW contributed to literature search, writing and editing of all sections of the review paper. XC, YX, and YG made significant contributions to the conception and design of the manuscript. JW created Tables 1,2 and Fig. 1. XC, YX, and YG undertook a critical review of the entire intellectual content of the manuscript and ultimately approved the version for publication. YG was responsible for ensuring that the descriptions are accurate and agreed by all authors. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

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This research received no external funding.

The authors declare no conflict of interest.