Role and regulation of kinases in age-related macular degeneration

Abstract

Background

Age-related macular degeneration (AMD) is the leading cause of chronic blindness in the elderly and causes retinal pigment epithelium (RPE) and photoreceptor cells to degenerate and die. However, the specific pathogenic mechanism of AMD has yet to be explored. The development of new AMD therapeutics is urgently required.

Main body

Studies have shown that kinases are increasingly important in AMD pathogenesis and treatment. Inhibition of apoptosis in retinal cells, such as RPE cells, maintenance of normal cellular metabolism, and preservation of normal autophagy are among the pathways involved in treating AMD. This is associated with kinase-related pathways, such as the PI3K/Akt, MAPK/ERK, JAK/STAT, mTOR, Ang-Tie, and AMPK signaling pathways.

Conclusions

In this review, we highlight recent advances in kinase-related pathways in treating AMD, to provide new directions for the prevention and treatment of AMD.

Introduction

Age-related macular degeneration (AMD) is one of the leading causes of vision loss and irreversible blindness in the elderly, severely compromising visual health [1]. Researchers predict that the number of people with AMD worldwide will reach 288 million by 2040 [2]. The main clinical manifestations of AMD are visual degeneration and impairment. Irreversible damage to retinal pigment epithelium (RPE) cells by reactive oxygen species (ROS) may destroy the normal structure and function of photoreceptors, leading to irreversible blindness [3]. Patients with AMD were divided into: dry AMD (dAMD) and neovascular AMD (nAMD). The former is characterized by geographic atrophy, often associated with slow vision loss, and accounts for approximately 90% of AMD patients. Patients in the latter group developed choroidal neovascularization (CNV). Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are currently the mainstay treatment for nAMD. However, several problems remain, including poor therapeutic efficacy and disease recurrence. Therefore, the development of new AMD therapeutics is urgently required. The study of kinase-related pathways plays an increasingly important role in AMD pathophysiology, providing a new idea for the prevention and treatment of AMD.

The phosphatidylinositol 3-kinases/protein kinase B (PI3K/Akt) signaling pathway is one of the most frequently activated signaling pathways in human cells [4]. It can play an important role in the pathogenesis of AMD by regulating cell survival, apoptosis, and angiogenesis [5]. The mitogen-activated protein kinase (MAPK) signaling pathway can protect RPE cells from apoptosis caused by oxidative stress by downregulating the expression of inflammatory factors, such as interleukin-6 (IL-6) and IL-8. It can also affect VEGF expression, inhibit abnormal neovascularization, and slow the occurrence of nAMD. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway inhibits apoptosis in RPE cells by acting on the expression of factors such as LIF. It also inhibits VEGF expression and reduces CNV production. The JAK/STAT signaling pathway represents potential as a target in preventing and treating AMD. The mammalian target of rapamycin (mTOR) enhances phagocytosis of RPE cells and acts on antioxidant factors such as nuclear factor erythroid 2-related factor 2 (Nrf-2) to counteract oxidative stress and protect RPE cells. This is a promising clinical prospect in AMD treatment. The angiopoietin/angiopoietin receptors (Ang/Tie) pathway acts extensively on VEGF, affecting neovascularization and thus inhibiting the development of nAMD. The AMP-activated protein kinase (AMPK) actively acts on antioxidant-related factors such as peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) and sirtuin-1 (SIRT1) as a means of alleviating oxidative stress and inhibiting apoptosis in RPE cells. It can also prevent and control AMD development by regulating normal autophagy in RPE cells. Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), which belongs to the serine/threonine protein kinase family, induces AMPK activation through phosphorylation, thereby mediating the improvement of ROS-induced mitochondrial dysfunction and playing a key role in the AMD signaling pathway [6].

PI3K/Akt signaling

The PI3K family of lipid kinases can be divided into three classes: I, II, and III [4]. Class I PI3K can be further divided into subgroups IA and IB. Class II PI3K catalyzes the generation of Phosphatidylinositol-3-phosphate and phosphatidylinositol (3,4)-bisphosphate from phosphatidylinositol (PI) and phosphoinositide (PIP) and can be further divided into α, β, and γ isoforms. Human class III PI3K is a threonine/serine kinase, and only PI3K is expressed in eukaryotic cells [5]. Akt is a serine/threonine 9-kinase that can be classified into PKB-α (Akt1), PKB-β (Akt2), and PKB-γ (Akt3), which are located in the center of the PI3K pathway and are widely involved in normal life processes such as cell proliferation, metabolism, survival, apoptosis, and angiogenesis [5, 7]. The PI3K/Akt pathway is one of the most frequently activated signaling pathways [4]. Cellular resistance to oxidative stress is closely linked to regulation of the PI3K/Akt signaling pathway [8]. The PI3K/Akt pathway is widely used for cell survival, apoptosis, and angiogenesis, and plays an important role in AMD development [5].

Survival

Cell survival is the basis of normal cellular activities, and is mainly involved in cell migration, apoptosis, and autophagy. Survival of RPE cells is associated with AMD. Researchers found that the activation of Akt facilitates the inhibition of sodium iodate (an established oxidizing agent for inducing an AMD-like phenotype in RPE cells, SI)-induced apoptosis in RPE cells [9]. Activated Akt protects RPE cells against oxidative damage [10]. PI3K, a direct upstream regulator of Akt, is closely related to the protective effects of Akt activation [11]. Therefore, the PI3K/Akt pathway is an important target to promote RPE cell survival for AMD prevention and treatment [10].

First of all, cell migration is the basis of many important physiological processes in organisms, reflects cell survival, and is closely associated with AMD onset and development [12]. For example, Isorhamnetin acts on the Akt/glycogen synthase kinase 3β (GSK-3β) pathway through Nrf-2, downregulates the expression of p-Akt and phosphorylated GSK-3β (p-GSK-3β), inhibits cell migration, and slows down the epithelial-mesenchymal transition (EMT) process in RPE cells [13]. EMT of RPE has a significant contribution to the pathogenesis of AMD [13]. Similarly, epigallocatechin gallate (EGCG) downregulates platelet-derived growth factor-BB (PDGF-BB)-induced phosphorylation of the PDGF-β receptor, downstream PI3K/Akt, and MAPK, and inhibits human RPE cell migration [12].

Secondly, we know that RPE apoptosis is significantly associated with AMD development [3]. In addition to affecting RPE cell migration, EGCG can also inhibit RPE cell apoptosis by acting on Akt, which complements AMD prevention and treatment [14]. The addition of EGCG to mouse RPE cells enhances the phosphorylation of Akt serine 473 (Ser473) and phosphorylated Ser380 sites of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), inhibits the phosphorylation of Ser9 site of GSK-3β, and exert an inhibitory effect on apoptosis [14]. Fan et al. found that Circular RNA caspase recruitment domain family member 6 (circ-CARD6) inhibits apoptosis by competing for microRNA-29b-3p (miR-29b-3p), acting on peroxiredoxin 6 (PRDX6), and regulating the miR-29b-3p/PRDX6/PI3K/Akt axis in hydrogen peroxide (H₂O₂)-induced oxidative stress in human retinal pigmented epithelial (ARPE-19) cells [15]. Glycyrrhizin inhibits apoptosis and autophagy in RPE cells via the miR-29b-3p/PRDX6/PI3K/Akt axis in SI-induced oxidative stress-induced mice and protects ARPE-19 cells by upregulating the phosphorylation of Akt and expression of Nrf-2 and heme oxygenase-1 (HO-1) [16].

Furthermore, various substances exert protective effects on RPE cells by acting on the PI3K/Akt pathway and promoting RPE cell survival. Ma et al. found that farrerol-induced phosphorylation of Akt and MAPK in ARPE-19 cells can downregulate the expression of B-cell lymphoma-2 associated X protein/B-cell lymphoma-2 (Bax/Bcl-2), cleaved caspase-3, polymerase, caspase-8, and caspase-9 proteins, and upregulated Nrf-2, which protected RPE cells by stimulating the expression of antioxidant enzymes such as HO-1, nicotinamide adenine dinucleotide phosphate quinone dehydrogenase-1 (NQO1), and glutamate-cysteine ligase modifier subunit [17]. Alpha-mangostin inhibits PI3K expression and Akt phosphorylation in SI-treated RPE cells [18]. It downregulates the levels of cleaved caspase-3, PGC-1, and SIRT3 proteins, and regulates the PI3K/Akt/PGC-1 pathway-mediated SIRT3 expression to play an important role in RPE cells [18]. Because SIRT3 expression exerts protective effects on RPE cells. Autophagy is essential for removing self-harmful substances from RPE cells damaged by ROS and has been implicated in AMD pathogenesis [19]. Ghosh et al. found that the normal phagocytosis and autophagy of RPE cells are associated with the Akt2/SIRT5/transcription factor EB (TFEB) pathway and that Akt2 inhibits the action of PGC-1 alpha (PGC-1α), which in turn reduces the expression of SIRT5, upregulated TFEB, and promote autophagy and phagocytosis by lysosomes, thereby protecting RPE cells [20].

As stated above, damage to RPE cells is closely related to AMD development, and therefore, protecting RPE cells can help prevent AMD development. The PI3K/Akt-related pathway showed significant protective effects on injured RPE cells by affecting cell migration, apoptosis, and autophagy, thus providing a broad scope for the treatment of AMD.

Oxidative stress and immune-inflammatory responses

Previous studies have shown that cellular damage is an important pathological mechanism underlying AMD [21]. By regulating the PI3K/Akt/Nrf-2 pathway, triptolide can protect RPE cells from SI-induced oxidative damage inhibiting ROS generation, and promoting the synthesis of antioxidant factors (HO-1 and NQO1) [8]. Peng et al. use the human amniotic mesenchymal stem cells conditional medium and exosomes to act on H₂O₂-induced APRE-19 cells [22]. In ARPE-19 cells, significant upregulation of p-Akt, phosphorylated PI3K (p-PI3K), and phosphorylated forkhead box O3 (FoxO3) was detected [22]. Additionally, ROS generation was inhibited. This suggests that the activation of the PI3K/Akt/FoxO3 pathway may benefit RPE cells by counteracting the harsh oxidative damage environment [22]. These studies, from the perspective of PI3K/Akt pathway inhibiting ROS generation and protecting RPE cells, provided a new direction for preventing AMD.

Researchers found that immune-inflammatory response is closely related to the development of AMD. Among these, the effects of inflammatory factors and immune cells such as IL-6 and neutrophils were significant [23, 24]. Gong et al. found that upregulation of IL-6 in the eyes of AMD patients modulates the PI3K/Akt/mTOR pathway, promotes phosphorylation of SIRT1, and inhibits deacetylation of Early 2-factor transcription factor 1. This change, in turn, induces low expression of the chromatin-binding protein and high-mobility group AT-Hook 1, reduces the level of nicotinamide adenine dinucleotide phosphate (NADPH), and inhibits the antioxidant capacity of retinal cells, leading to apoptosis of RPE cells [25]. Ultimately, RPE apoptosis leads to the formation of AMD. Concurrently, in a mouse model of AMD, downregulation of Akt2 inhibited interferon (IFN-)-λ, inhibiting Lipocalin 2-induced neutrophil infiltration and delaying the development of AMD symptoms in mice [24].

To date, repairing RPE damage caused by oxidative stress and immune dysregulation has been a hot research topic in AMD via the PI3K pathway.

Neovascularization

CNV is a major manifestation of nAMD and is associated with central vision impairment in AMD patients [26]. The PI3K/Akt pathway is a therapeutic target for neovascular diseases such as AMD [4]. In a series of cellular experiments, the PI3K/Akt pathway has demonstrated a critical ability to inhibit CNV. First, researchers found that pigment epithelial-derived factor-small extracellular vesicles can downregulate the levels of VEGF-induced phosphorylated ERK (p-ERK) and p-Akt then inhibit the proliferation and migration of endothelial cells (ECs) [27]. ECs are closely associated with neovascularization in patients with nAMD [28]. In addition, evidence suggests that Colony Stimulating Factor 1(CSF1) and CSF1 Receptor (CSF1R) levels are increased in the eyes of patients with nAMD [29]. This finding offers a potential idea for nAMD treatment. Zhou et al. further found that hypoxia-induced human umbilical vein ECs can stimulate the PI3K/Akt/FoxO1 pathway by increasing CSF1 secretion, enhancing the CSF1–CSF1R interaction, activating the CSF1R/PI3K/Akt/FoxO1 pathway, and promoting macrophage migration. Thus, inhibition of the CSF1/CSF1R interaction may inhibit neovascularization, and this is a promising method for studying the pathology of nAMD [29]. Aflibercept regulates neovascularization via the VEGF/PI3KA/Akt/mTOR pathway. Aflibercept can downregulate the binding of VEGF to VEGF-receptor 2 (VEGF-R2) and inhibit the activation of the downstream PI3K/Akt/mTOR pathway. This further leads to the downregulation of the expression of PI3KA in human vascular ECs. This may inhibit the conversion of PIP2 to PIP3 and the generation of neovascularization [30]. Last, inhibiting the progression of nAMD. In addition, Aflibercept also downregulates phosphorylated STAT3 (p-STAT3) and IL-6, inhibiting the expression of MMP14 [30]. This study also contributes to the clinical management of nAMD.

Inhibition of CNV by the PI3K/Akt pathway has also been demonstrated in an animal experiment [31]. Kong et al. induced CNV production in mice by laser and subsequently injected EV11 (a novel aryl ketone amide) into the vitreous cavity of mice and found that EV11 can inhibit the activation of Akt and ERK1/2 pathways to affect the activity of ECs, thus inhibiting CNV production [31]. Studies on various PI3K/Akt-related pathways targeting the inhibition of neovascularization have made significant progress, providing a potential platform for the clinical treatment of nAMD [4].

MAPK/ERK signaling

Evidence suggests that the MAPK pathway is essential in normal life processes, such as cell proliferation, differentiation, survival, and apoptosis [32]. The MAPK signaling pathway is classified into four distinct groups: extracellular signaling regulators ERK1/2, c-Jun N-terminal kinase 1/2/3 (JNK1/2/3), p38 MAPK (α, β, γ, and δ), and ERK5 [33]. MAPK is a family of intracellular serine-threonine protein kinases and can be activated by many extracellular stimuli such as hormones, oxidative stress, ultraviolet radiation, and hypoxia [34]. MAPK regulates various cellular processes involving inflammation, cell proliferation, and differentiation [32]. ERK is an effector kinase in the triple kinase cascade reaction, is highly specific, and plays an important role in processes such as cell survival and differentiation [35]. The ERK pathway is the first MAPK cascade to be elucidated and plays a central role in the MAPK pathway network in regulating cell proliferation, differentiation, and survival [36]. MAPK signaling is involved in the pathogenesis of neurodegenerative diseases such as AMD and can influence the survival of photoreceptor cells [36].

Survival

Senescence, damage, and apoptosis of RPE cells are associated with the main causative factors of vision loss in patients with developing AMD. Therefore, finding effective and feasible ways to protect damaged RPE cells against AMD is necessary. Researchers have performed an unlinked disequilibrium genome enrichment analysis of the AMD and MAPK pathways and confirmed the correlation between the genes involved [37].

First, normal mitochondrial function is closely related to cell survival; therefore, maintaining normal mitochondrial function in RPE cells can help prevent AMD [38, 39]. For example, the results of the study showed that through the p38 and ERK MAPK pathways, quercetin (a polyphenol) can downregulate the expression of IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) and protect normal mitochondrial function in ARPE-19 cells [40]. Tsou et al. found that lemon peel ultrasonic-assisted water extract (LUWE) inhibits SI-induced expression of the pro-fission proteins phosphorylated drop-1 (p-drop-1) and Fis1, as well as downregulates phosphorylated MEK-1/2 (p-MEK-1/2) and p-ERK-1/2 in ARPE-19 cells. ERK-1/2 in ARPE-19 cells protects the mitochondria from fission and thus inhibits the apoptosis of RPE cells [41]. Abnormal apoptosis of RPE cells is an important trigger for AMD pathogenesis [3].

Secondly, we discuss the possible applications of RPE apoptosis and the MAPK/ERK pathway in AMD treatment [3]. A previous report revealed that EUK-134 (a superoxide dismutase and catalase mimic) can upregulate the expression of Bcl-2 protein; inhibited the expression of p-ERK, p-p38, phosphorylated JNK (p-JNK), phosphorylated p53 (p-p53), Bax, and cleaves caspase-3 in ARPE-19 cells; and inhibited the expression of p-ERK, p-p38, p-JNK, p-p53, Bax, and cleaved caspase-3 by EUK-134 in SI-induced AMD model, in vitro [38]. EUK-134 prevent SI-induced retinal deformation by inhibiting RPE cell apoptosis [38].

Furthermore, Wu et al. found that amyloid β42, a major component of drusen, activates microglia, activates the p38 MAPK signaling pathway, upregulates the pro-inflammatory cytokines IL-1β and cyclooxygenase-2 (COX-2), and triggers apoptosis in photoreceptor cell 661W [42]. Abnormal apoptosis of photoreceptor is also a key factor in AMD pathogenesis [42]. This is related to the MAPK/ERK pathway [42]. The MAPK/ERK pathway is expected to protect damaged RPE cells and delay photoreceptor degeneration, a promising treatment for AMD [42].

Oxidative stress and immune-inflammatory responses

Loss of retinal cell function and structural damage due to external barriers, such as inflammatory responses and oxidative stress [43], impedes AMD treatment.

First, the role of multiple substances in inhibiting the inflammatory response and protecting RPE cells through MAPK-related pathways was demonstrated. This lays the foundation for further therapeutic research in AMD. For example, Luteolin inhibits the nuclear translocation of nuclear factor kappa-B (NF-κB) by promoting the phosphorylation of Akt, thereby blocking the MAPK inflammatory pathway and the NF-κB signaling pathway to protect the receptors of IL-κB. And Luteolin attenuates IL-1β-stimulated IL-6, IL-8, soluble ICAM-1, MCP-1, and other inflammatory response-associated factors in ARPE-19 cells [43]. In addition, nepetin (a flavonoid compound) acts on the IL-1β-induced inflammatory response in ARPE-19 cells, inhibits the activation of NF-κB and MAPKs, and downregulates the expression of the inflammatory factors IL-6, IL-8, and MCP-1 to protect RPE cells [44]. These factors have been linked to the protective effects of RPE cells and have been studied for their potential in preventing AMD [43].

IL-17A activate NOD-like receptor thermal protein domain- associated protein 3 (NLRP3) inflammatory vesicles and upregulate IL-1β expression by promoting the phosphorylation of Akt, ERK1/2, p38 MAPK, and NF-κB p65 in RPE cells, which in turn affects ROS production [45]. This favors the protection of RPE cells. And it is an important way to study the replication of AMD formation [45]. Blockade of NF-κB attenuates IL-17A-induced IL-1β expression [45]. SI-treated ARPE-19 cells and mouse RPE cells undergo EMT in RPE cells, which is closely related to AMD formation. Yang et al. showed that treating ARPE-19 cells and mouse RPE cells with the ERK-specific inhibitor FR180204 significantly inhibits the EMT tendency of RPE cells and reduces ROS generation, which may protect RPE cells [46]. Researchers have found that PRDX6 upregulates epidermal growth factor receptor (EGFR) expression in ARPE-19 cells with H₂O₂-induced oxidative damage, increases the phosphorylation levels of EGFR and ERK to a certain extent, activates the EGFR/ERK signaling pathway, and reduces the generation of ROS to protect RPE cells [47]. Protecting RPE cells is an essential aspect of advancing AMD prevention and treatment.

In recent years, with the booming research on the MAPK signaling pathway, precision therapy, especially the cellular immune inflammatory response and oxidative stress-based therapy, has opened up new ideas and pathways for treating AMD. It is expected to protect damaged RPE cells, a promising treatment for both wet and dry AMD [44, 45].

Neovascularization

The retina undergoes morphological changes upon external stimulation to form CNVs that play a role in AMD pathogenesis [48].

Researchers examined the expression of apolipoprotein E receptor-2 (APOE2), VEGF, basic fibroblast growth factor (b-FGF), IL-1β, and IL-6 in the retinal lysate of a mouse model of laser injury as well as the expression levels of MAPK proteins such as p38, JNK, and ERK in ARPE-19 cells. Downregulation of MAPK-related genes may inhibit the expression of VEGF, PDGF-BB, b-FGF, and related inflammatory cytokines, and affect the development of nAMD [48]. Therefore, the expression of MAPK pathway-related proteins is significantly associated with nAMD development and deserves further investigation [48].

Li et al. inhibited the expression of the allograft inflammatory factor 1 (AIF-1) gene by intravitreal injection of AIF-1 siRNA in a mouse model of laser-injured CNV, downregulated AIF-1 protein, and inhibited the expression of MAPK p44/42. This has slowed the development of CNV and conferred clinical application value for nAMD treatment [49]. Another study demonstrated that by inhibiting Akt, ERK1/2, and p38-MAPK phosphorylation, sanguinarine chloride (SC) can downregulate VEGF expression, inhibit neovascularization, and play a therapeutic role in CNV, both in vivo and in vitro [50]. This is critical for the clinical management of nAMD. In addition, Cornebise et al. found that red wine extract (RWE) can inhibit the phosphorylation of MEK and ERK 1/2, inhibit the action of VEGF-A, affect the secretion of vascular endothelial growth factor-R2 in the AMD model, in vitro [51]. This provided a broad direction for the prevention and treatment of nAMD.

The therapeutic approach of Targeting VEGF and inhibiting neovascularization through the MAPK/ERK pathway has become a hotspot for nAMD treatment.

JAK/STAT signaling

The JAK/STAT signaling pathway is an evolutionarily conserved transmembrane signal transduction mechanism. It directly regulates communication from receptors to the nucleus, thereby promoting the transcription and activation of target genes [52, 53]. The three main components of the JAK/STAT signaling pathway are tyrosine kinase-associated receptors, JAK, and STAT [53]. The JAK family comprises a group of non-transmembrane tyrosine kinases consisting of four members: JAK1, JAK2, and others. The STAT family comprises seven members: STAT1-4, STAT5A, STAT5B and STAT6 [54]. Various cytokines, including IL, VEGF, and IFN, bind to their corresponding receptors and subsequently lead to dimerization of receptor molecules. This process enables JAK to bind and phosphorylate receptors [53]. Subsequently, STAT is activated and phosphorylated, forming dimers and undergoing translocation to the nucleus [55]. Finally, the STAT dimer binds specific DNA sequences and initiates transcription. Thus, the JAK/STAT signaling pathway regulates the expression of various genes and plays a biological role. The suppressor of cytokine signaling (SOCS), AG490 (a JAK inhibitor), and other factors can inhibit the JAK/STAT signaling pathway [53, 55]. The JAK/STAT signaling pathway is closely associated with the pathological process of AMD through its biological functions related to cell survival, oxidative stress, neovascularization, and inflammation, thus presenting a promising avenue for clinical applications and insights into the prevention and treatment of AMD [54, 56–59].

Survival

By integrating extrinsic and intrinsic signals, and through cross-talk involving STAT3 with other signaling pathways, such as the toll-like receptor (TLR), wingless-type MMTV integration site family (Wnt), and VEGF signaling, the JAK/STAT pathway regulates RPE survival and biological activities [60–62]. STAT3 upregulates several pro-survival genes. Gritsko et al. revealed that STAT3 directly upregulates baculoviral inhibitor of apoptosis repeat-containing 5 gene expression [63]. Catlett-Falcone et al. demonstrated that STAT3 signaling upregulates Bcl-extra-large (Bcl-xl) expression [64]. So upregulation of STAT3 protects RPE cells from injury, thereby decelerating the pathological process of AMD [65]. Additionally, the JAK/STAT signaling pathway influences cell survival and the pathology of AMD by regulating various processes, including differentiation and apoptosis [56, 57].

The JAK/STAT signaling pathway regulates cell differentiation. Understanding differentiation is crucial for advancing direct differentiation of retinal stem cells/progenitors for treating AMD in vitro or in vivo stem cell approaches [66]. Bhattacharya et al. demonstrated that retinal stem/progenitor cell differentiation along rod photoreceptor cell lines in vivo is facilitated by the attenuation of JAK/STAT and Notch signaling pathways [66]. Chen et al. demonstrated that LINC00167 inhibits the JAK/STAT signaling pathway via the LINC00167/MicroRNA-203a-3p/SOCS3 axis, thereby maintaining RPE differentiation and protecting against AMD [56]. Wang et al. successfully generated and differentiated induced pluripotent stem cells (iPSCs) derived from an AMD patient into RPE cells that expressed the characteristic markers. This suggests the potential of this approach as a regenerative strategy for AMD [67]. The findings of these studies indicate that the modulation of RPE differentiation may represent a potential strategy for treating AMD.

One potential strategy for maintaining retinal morphology and functionality and impeding AMD’s pathological progression is inhibiting photoreceptor apoptosis. The JAK/STAT signaling pathway functions as an interferon in cells and is regarded as a pivotal pathway for cytokine signaling during apoptosis [68]. The JAK-STAT signaling pathway plays a key role in both pro- and anti-apoptotic mechanisms. For example, STAT1 augments the transcriptional activity of p53 on several p53-responsive pro-apoptotic genes, while concurrently exerting a negative regulatory influence on the Bcl-xl promoter [68]. JAK2 and STAT3 have been identified as players in photoreceptor apoptosis during retinal degeneration [69]. In Drosophila, ectopic activation of JAK/STAT signaling by Maheshvara stabilizes hop transcripts, leading to hid-mediated apoptosis in photoreceptor neurons [70]. Liang et al. found that in diabetic retinopathy, STAT3 activation tilts the balance toward pro-apoptotic outcomes in RPE cells by simultaneously upregulating Bax expression and cysteinyl aspartate-specific proteinase levels while suppressing Bcl-2 in retinal cells [71]. STAT3 also exhibits antiapoptotic activity [54]. Dong et al. demonstrated that leukemia inhibitory factor (LIF) can inhibit apoptosis and oxidative stress by targeting the STAT3 signaling pathway [57]. Humanin activates STAT3 phosphorylation to inhibit cysteinyl aspartate-specific proteinase-3 activation and reduce apoptosis in RPE cells exposed to oxidative stress [72]. This suggests the potential for developing AMD treatments based on apoptosis.

Oxidative stress

Oxidative stress causes damage to susceptible RPE cells. Oxidative damage to the retina may also contribute to AMD development. It is well established that RPE cells are particularly vulnerable to oxidative damage owing to their high oxygen consumption.

The effects of N-acetyl-cysteine and the JAK2/STAT3 signaling pathway inhibitor AG490 on RPE cells exposed to high glucose conditions were investigated by Li et al. They demonstrated that oxidative stress is an upstream factor that affects STAT3 activity, leading to transcriptional activation of VEGF [60], and VEGF induces CNV in AMD eyes [73]. Oxidative stress contributes to CNV in AMD [73]. Fragoso et al. demonstrated the involvement of STAT3 in mediating Wnt-dependent protection of RPE cells during oxidative stress injury [62]. Additionally, STAT3 signaling is a critical mediator of TLR3-regulated protection of RPE cells [61]. Furthermore, Dong et al. demonstrated that LIF can inhibit apoptosis and oxidative stress by targeting the STAT3 signaling pathway, thereby alleviating oxidative damage in cone cells [57]. These findings indicate that the JAK/STAT signaling pathway may serve as a potential target for mitigating oxidative damage and protecting RPE cells, thereby influencing the pathological process of AMD.

Neovascularization

Multiple factors influence neovascularization, which subsequently affects AMD pathogenesis. STAT3 is an upstream activator of VEGF [58]. VEGF promotes choroidal neovascularization and is a key pathogenic factor in the development of nAMD [74]. Dentelli et al. observed phosphorylated STAT5 in certain endothelial cells treated with IL-3. These findings suggested that STAT5 is involved in neovascularization [54].

Inhibition of the JAK/STAT signaling pathway may be an effective method for inhibiting neovascularization. For instance, chrysin blocks IL-6-induced neovascularization by suppressing the soluble IL-6 receptor/gp130/JAK1/STAT3 signaling axis [75]. Furthermore, the research of Tu et al. indicated that tocilizumab, a monoclonal antibody, can reduce the formation of CNV and inhibit the leakage of CNV lesions. This is accomplished by regulating macrophage polarization via inhibiting the STAT3/VEGF axis [58]. The peptide R9–SOCS3-KIR has the sequence RRRRRRRRRLRLKTFSSKSEYQLVV. R9–SOCS3-KIR blocked IL-6-mediated nuclear translocation of Phosphorylated STAT3 (p-STAT3), thereby inhibiting overactivation of STAT3. This overactivation leads to elevated VEGF-A levels and contributes to CNV [76]. These findings suggest that inhibiting neovascularization via the JAK/STAT signaling pathway may represent a potential therapeutic strategy for treating AMD.

Immune-inflammatory responses

It is widely acknowledged that under specific pathological conditions, the inflammatory process is a protective mechanism initiated by the body in response to pathogen attack or damage [53]. Local inflammation plays an important role in AMD pathogenesis. However, systemic inflammation may also involve this process [77]. Inflammasomes are cytosolic, multiprotein complexes. The nucleotide-binding oligomerization domain-like receptor protein 3 is an inflammasome that is critically involved in the pathogenesis of retinal degenerative disorders [78]. Studies have demonstrated that JAK/STAT signaling components are expressed or activated in human RPE cells exposed to inflammatory cytokines and choroidal neovascular membranes in AMD patients [77]. IFN-γ is an inflammatory mediator. Wei et al. have largely confirmed that IFN-γ induces ferroptosis in ARPE-19 cells by activating the JAK1-2/STAT1/SLC7A11 signaling pathway in IFN-γ-treated mice [79]. Notably, STAT3 plays a dual role in inflammation, mediating both anti-inflammatory and pro-inflammatory effects [80, 81]. Antonia et al. identified that STAT3 indirectly suppresses tumor necrosis factor-induced chemokine production (C-C Motif Chemokine Ligand 2, C-X-C Motif Chemokine Ligand 1, and C-X-C Motif Chemokine Ligand 10) by upregulating the ubiquitin-modifying enzyme TNFAIP3/A20, thereby limiting inflammation [80]. p-STAT3 activation in microglia is associated with neuroinflammation and exacerbates retinal damage [81]. The JAK/STAT pathway is activated by proinflammatory cytokines (e.g., IL-1 and IL-6) and exhibits sustained phosphorylation of STAT3-Tyr705 in degenerating retinas, driving inflammation [82]. In conclusion, the JAK/STAT pathway is closely associated with the inflammatory response and thus plays a pivotal role in the pathogenesis of AMD.

The JAK/STAT signaling pathway inhibition is a promising target for AMD treatment. For instance, the kinase inhibitory region of the suppressor of cytokine signaling 1 suppresses the effects of IFN-γ (IL-12) and IL-17 by binding to JAK2 [83, 84]. IL-17 could be involved in the pathogenesis of wet AMD by promoting neovascularization [85]. Another example is that of R9–SOCS3-KIR [76] and AG490 [86]. R9–SOCS3-KIR inhibits STAT3 signaling, thereby suppressing downstream effectors such as IL-17 and VEGF-A [76]. AG490 is a JAK2–STAT3 inhibitor that reduces STAT3 phosphorylation. This inhibition decreases the production of inflammatory factors, such as tumor necrosis factor-α and IL-6, thereby reducing inflammation [86], and inflammation contributes to AMD pathogenesis. The modulation of inflammation through the JAK/STAT pathway may represent a potential therapeutic avenue for AMD treatment (Fig. 1).

Fig. 1.

The known pathways through which JAK/STAT acts on AMD. The figure illustrates the pathways of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway and its inhibitors in retinal pigment epithelium (RPE) cells during the pathological process of age-related macular degeneration (AMD). The JAK/STAT signaling pathway regulates various effects, including oxidative stress, inflammation, and neovascularization, primarily through STAT1 and STAT3, thus exerting different effects on the development of AMD. Furthermore, research has demonstrated that STAT5 is associated with neovascularization

mTOR signaling

Brown et al. first identified mTOR as a target of rapamycin (TOR) in mammalian cells in 1994 [87]. It is critical in assembling two protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). High levels of mTORC1 and mTORC2 can imply that the mTOR signaling pathway is active and activated [88]. And mTOR is the core molecule that regulates cellular mechanisms associated with AMD (Fig. 2), such as cellular survival, apoptosis, growth, metabolism, and autophagy [89, 90].

Fig. 2.

The known pathways through which mTOR acts on AMD. mTOR: the mammalian target of rapamycin; AMPK: 5′-adenosine monophosphate-activated protein kinase; PI3K: phosphoinositide 3-kinase; PIP3: 3-phosphoinositide; Akt: protein kinase B; p70S6K: protein S6 kinase; ULK1: unc-51 like autophagy activating kinase 1; miR-626: microRNA-626

Survival

The mTOR signaling pathway is vital for cellular survival and inhibits apoptosis by maintaining continuous activation. Previous studies have shown that the plasma levels of miR-626 in patients with AMD are significantly downregulated compared to plasma of miR-626 in healthy donors [91]. Another recent study identified that miR-626 causes apoptosis and macular degeneration in RPE cells through the mTOR signaling pathway via a large neutral amino acid transporter 1 [92]. Xie et al. carried out an experiment involving the transmission electron microscope and western blot to detect autophagy. Finally, they found that decorin protects the RPE cells from apoptosis, which is an indispensable pathological mechanism of AMD, by promoting autophagy via AMPK/mTOR [93].

Akt/mTOR signaling plays a key role in mediating the activation of Nrf-2 [94]. Nrf-2 has been recognized as a central regulator in countering oxidative stress by modulating the expression of multiple antioxidant proteins and inhibiting apoptosis, thereby representing an efficient defensive strategy for AMD [95–97]. Mechanistically, the activation of PI3K promotes the transformation of PIP3 from PI. PIP3 recruits, activates, and phosphorylates Akt, further activating the downstream kinase mTORC1 and stabilizing Nrf-2 by phosphorylating and inhibiting glycogen synthase kinase-3β. At this point, Lin et al. reported that triptonide, an effective Nrf-2 activator, can show promise as a potent antioxidant protective agent for AMD patients [98]. These suggest that the mTOR signaling pathway plays a crucial role in cellular survival by inhibiting apoptosis, which is regarded as a part of the RPE cell death mechanism causing AMD [99].

Neovascularization

Neovascularization is a critical cause of nAMD [100]. Previous research has demonstrated that rapamycin, an mTOR pathway inhibitor, effectively modulates endothelial tube formation in an in vitro model of nAMD, highlighting the potential of targeted mTOR inhibition in managing ocular neovascularization [101].

Immunoblotting experiments have indicated that the Akt/mTOR pathway is activated in fetal RPE cells overexpressing RNA demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) and that promoting CNV contributes to AMD [26]. Wu et al. proposed that in AMD, circular RNA-Uxs1 (circRNA-Uxs1) upregulates the expression of placental growth factor by binding to miR-335-5p, thereby activating the mTOR/p70S6K pathway [102]. Husain et al. reported that VEGF-A function is promoted by substrate stiffening via the PI3K/Akt/mTOR pathway [103]. Gáll et al. demonstrated a link between hemorrhage and AMD pathology through a retrospective clinical analysis [104]. Sghaier et al. found that Resvega®, a nutraceutical formulation, inhibits PI3K/Akt/mTOR signaling pathways and decreases VEGF-A secretion [105]. Latifi-Navid H and Soheili ZS prove by Network analysis the specific effect of Aflibercept is a decrease in VEGF/VEGF-R2 interaction, which leads to neovascularization by activating the PI3K/Akt/mTOR signaling pathway [30].

In terms of clinical treatment strategies, Xia et al. developed a novel biomimetic nano complex targeting the upstream factor of VEGF. This complex aims to address the problem of unsatisfactory therapeutic effects of mTOR inhibition of VEGF, which is probably caused by the established target of current therapy targeting only the downstream VEGF [106]. These studies provide a reliable reference for the specific pathological mechanisms and viable treatment options of AMD in which mTOR is involved.

Phagocytosis

RPE cells are responsible for phagocytosis of shed photoreceptor outer segments [107]. Inana et al. first proved that RPE phagocytic dysfunction plays an important role in AMD [108]. Voisin et al. analyzed phagocytic activity and suggested that damage leading to AMD occurs at the level of the RPE, which can partially impair phagocytic function. They demonstrated that certain proteins’ involvement is essential for phagocytic activity, among which the mTOR pathway is vital [109].

Go et al., through experimental analysis, reported that the RPE develops an expanded endolysosomal compartment to ensure highly efficient phagocytosis. However, an increase in lysosomal mass could lead to mTOR activity, which could cause further problems [110]. Chen et al. silenced the circular noncoding RNA NR3C1 (circNR3C1) may interrupt phagocytosis and promote RPE proliferation by blocking the Akt/mTOR pathway [111]. Saito researched the relationships between Nrf-2 and phagocytosis progression of POS and unexpectedly found that the activator of Nrf-2, resveratrol sulfatide 9, can activate the AMPK/mTOR signaling pathway earlier than p62 induction [112]. This elucidates the role of Nrf-2 activation in the pathogenesis of AMD related to mTOR. Combining these results, the phagocytic function of RPE cells related to the mTOR signaling pathway is a key element in the complex pathological process of AMD.

Autophagy

Autophagy is a cellular self-digestion process involving intracellular component degradation [113]. In the pathological process of AMD, impaired autophagy promotes the accumulation of extracellular drusen, which is the main cause and feature of dAMD [114]. Using methods of metabolomic, Belete et al. reported that metabolic dysregulation, which leads to dysfunctional autophagy, is one of the pathological mechanisms of AMD [115]. Kim found that mTOR is integral for autophagy regulation as the central factor up and down [116].

AMPK is a well-known mTOR inhibitor that induces autophagy [117]. Kim found that AMPK directly activates autophagy by phosphorylating ULK1, while mTOR inhibits autophagy by phosphorylating ULK1 to disrupt the AMPK/ULK1 interaction as the central factor [118]. Zhang et al. reported mTOR pathway hyperactivity in AMD RPE, evidenced by elevated phosphorylated mTOR (Ser2448), total mTOR, and sustained activation of its downstream target p70S6K. This mTOR overactivation impairs autophagy termination via ULK1 phosphorylation and lysosomal dysfunction, driving AMD pathogenesis [119]. Yang et al. determined the effects of the AMPK/mTOR/ULK1 pathway SIRT3 in RPE cells [120]. These studies provide references for the treatment of the ocular disease AMD. Chen et al. demonstrated that glucosamine (GlcN) induces autophagy in ARPE-19 cells in vitro primarily via the AMPK/mTOR signaling pathway, highlighting its therapeutic potential for AMD [121]. Vessey et al. carry on the treatments targeting autophagy and propose that metformin may cause the inhibition of mTOR expression by enhancing the turnover of microtubule-associated protein 1 light chain 3 isoform II via ATM/AMPK signaling pathway, this further ameliorates the AMD phenotype in mice lacking APOE [122].

The level of Sequestosome1 (p62/SQSTM1) is commonly regarded as an indicator of autophagy [123, 124], it acts upstream in the regulation of mTOR [125, 126]. Studies have reported that in RPE cells, p62 is involved in the formation of macromolecular complexes associated with autophagy activation via mTOR suppression [127]. Liu et al. demonstrated that by inhibiting the phosphorylation of mTOR, the suppressor of cytokine signaling 2 overexpression can enhance autophagy in RPE cells [128]. This provides a potential therapeutic approach for AMD. These studies show that the role of mTOR in regulating autophagy is vital to AMD pathology, and targeting the mTOR pathway to enhance autophagy could be a promising therapeutic strategy for treating AMD.

Other kinase pathways

The Ang/Tie pathway is involved in a multistage angiogenic cascade involving two type-I tyrosine kinase receptors (Tie1 and Tie2) and four ligands (Ang-1, Ang-2, Ang-3, and Ang-4). Tie1 and Tie2 are predominantly expressed in the endothelium. Tie1 acts on Ang-1 and Ang-2 and regulates their interactions with Tie2. Tie1 acts on Ang-1 and Ang-2 and regulates their interaction with Tie2 [129]. Ang-2 is extensively found in ECs and can act on the Ang-2/Tie2 pathway to upregulate FoxO1, downregulate the expression of Tie1 and Tie2, and in turn affect factors involved in neovascularization of nAMD, such as VEGF [129]. AMPK is widely known as a cellular energy sensor because it undergoes metastasis when bound to AMP and reflects energy stress caused by changes in the ratio of AMP, ADP, and ATP [130]. There is a link between AMD-related cellular senescence. In conclusion, the AMPK pathway is a multi-signal transduction pathway that regulates energy homeostasis. Furthermore, evidence suggests that AMPK activation can positively influence the aging process and affect cellular autophagy, which is important in treating AMD [131]. CaMKII belongs to the serine/threonine protein kinase family [6]. Activated CaMKII induces AMPK activation through phosphorylation, thereby mediating the improvement of ROS-induced mitochondrial dysfunction and playing a key role in the AMD signaling pathway [6].

Survival

AMD has a variety of etiological factors, among which apoptosis and oxidative damage of normal retinal cells may be related to its pathological process. Researchers found that inhibition of src-homology 2 domain-containing phosphatase-1 (SHP-1) gene expression causes K63-linked ubiquitination and overactivation of interferon gene stimulating factor (STING), partially blocks the AMPK pathway downstream of STING, and promotes apoptosis in RPE cells [132]. This can lead to AMD as a cause of AMD. Others found that in SI-induced dAMD mouse models and ARPE-19 cells, CaMK2D (one of the major CaMKII proteins) influenced RPE cell apoptosis and the AMD pathological process by upregulating CFI expression [133]. Moreover, activated CaMKII affects its downstream molecule, CREB, which can mitigate optic nerve damage and provide protection for retinal ganglion cells (RGCs), offering potential for AMD treatment [134].

In addition, peroxisome PGC-1α, a downstream target of AMPK, is widely involved in cellular antioxidant activity and mitochondrial biogenesis, and its stable expression is associated with AMD [130]. Kaarniranta et al. showed that PGC-1α may attenuate oxidative damage and protect retinal cells by regulating the action of VEGF through AMPK and SIRT1, promoting mitochondrial biogenesis, and facilitating antioxidant enzymes and DNA damage responses [135]. The results of a study showed that klotho can regulate cellular mitochondrial and cellular activity by acting on the upstream signals of the AMPK/PGC-1α pathway, phosphorylating AMPK and p38 MAPK, activating cAMP-response element binding protein and transcription factor-2, and expressing PGC-1α [136]. Thus, the AMPK/PGC-1 α pathway contributes to the restoration of normal RPE cell activities and provides new ideas for AMD treatment [136].

Furthermore, previous studies have found that AMPK activity is reduced in the RPE of AMD patients, and that oxidative stress can cause DNA damage to a degree that downregulates NAD⁺ and SIRT1 expression [137]. Qu et al. investigated the therapeutic effect of metformin on AMD by using glyoxal to induce oxidative stress in ARPE-19 cells, thereby mimicking dAMD [137]. The results showed that metformin in acetaldehyde-induced ARPE-19 cells can counteract the oxidative damage occurring in ARPE-19 cells by increasing the NAD⁺/nicotinamide adenine dinucleotide (NADH) ratio, upregulating SIRT1, and then activating the SIRT1/AMPK pathway [137]. In addition, metformin activates AMPK, upregulates Nrf-2, and promotes its interaction with antioxidant response elements to regulate normal oxidative metabolism in RPE cells [137]. Consequently, the AMPK pathway plays a significant role in AMD treatment and prevention [137].

Neovascularization

Neovascularization occurs extensively in nAMD patients. It is associated with various factors, such as VEGF, Ang-1, and Ang-2, as well as growth factors, such as b-FGF, which are closely related to the development of nAMD [138].

RPE cells form monomolecular membranes via junctional proteins, and AMD disrupts these cellular junctions. This may trigger overexpression of VEGF, Ang-2, and tissue inhibitor of metalloproteinase-1 (TIMP-1). The researchers altered the area of the monomolecular layer of porcine RPE cells with polydimethylsiloxane templates to form a gradient of RPE detachment in proportions of 10, 25, and 50%. This result indicates an increase in angiogenic factor secretion as the degree of detachment increases. And this change can inhibit phagocytosis of POS by RPE cells, which is associated with the development of AMD [139]. After delivering lysosome-targeting chimeras (LYTAC) or LYTAC Plus via nucleic acid hydrogel, researchers found that Ang-2 and VEGF-R2 are significantly downregulated in the control group compared to the CNV group in the laser-injured nAMD mouse model [140]. This holds great clinical promise for nAMD treatment [140]. In addition, the current study confirmed that Ang-1-anti CD105-PLGA nanoparticles (AAP NPs) slow-release Ang-1 in a rat model of CNV can reduce neovascularization and inhibit Ang-2 secretion [141], thereby treating nAMD. Researchers changed the treatment regimen of 54 patients with nAMD from Aflibercept to Faricimab and found that VEGF-A is inhibited, while Ang-2 was significantly reduced, hindering further development of nAMD [142].

Ang and its mediated neovascularization play important roles in the pathogenesis of nAMD. Thus, the Ang-Tie pathway is significantly linked to neovascularization and is a potential target for nAMD treatment.

Autophagy

A link exists between AMD pathogenesis and abnormal cellular autophagy [131]. It has been shown that senescent RPE cells accumulate lipofuscin in lysosomes, inhibiting lysosomal enzymes and thus the process of cellular autophagy [117].

Zhang et al. found that PAPR2 expression is upregulated, NAD⁺ and SIRT1 expression is affected, PGC-1α acetylation is increased, and AMPK activity, as well as normal cellular autophagy, is inhibited in the RPE of AMD patients compared with normal RPE [119]. Researchers have used berberine, an alkaloid from Chinese herbs, to treat H₂O₂-induced oxidative damage in D407 (human RPE cell line) and primary human RPE cells. Berberine may promote autophagy in AMPK-activated cells to protect them [3]. Berberine’s positive effects are inhibited by autophagy inhibitor PIK-III or LC3B silencing, indicating it enhances autophagy in injured cells by activating the AMPK/mTOR/ULK1 pathway, providing a novel therapy for AMD [3].

In addition, ming-mu-di-huang-pill (MMDH pill), a traditional Chinese herbal medicine, can act on the AMPK/SQSTM1/Keap1 pathway to protect SI-induced RPE cells, increase antioxidant enzyme activities, slow down oxidative stress, and enhance autophagy in RPE cells, providing ideas for treating AMD [143]. Dieguez et al. found that unilateral superior cervical ganglionectomy can induce a mice model of dAMD, via decreasing RPE AMPK phosphorylation and reducing mitochondrial function [39]. Metformin restores this change via AMPK. Therefore, AMPK plays an indispensable role in maintaining mitochondrial homeostasis and regulating autophagy in RPE cells to prevent and control AMD development [39].

Discussion

The specific pathogenic mechanism of AMD remains poorly understood, and current treatment strategies are largely based on intravitreal injection of anti-VEGF drugs supplemented by laser therapy and other techniques. However, these approaches often exhibit suboptimal therapeutic efficacy and require repeated treatments. It is particularly important to seek new effective treatment pathways. The therapeutic role of kinases in various neurodegenerative diseases has been previously reported. However, no study has summarized the role of multiple kinase pathways in AMD. A growing number of studies have shown that various kinases, including PI3K, are involved in RPE cell proliferation, migration, and damage production, and the role of multiple kinases as diagnostic markers of AMD has been emphasized. This demonstrates the feasibility of targeting kinases to treat AMD patients. For example, the use of MAPK inhibitors in combination with other therapies has become a popular topic in the treatment of patients with AMD. Combination therapies targeting the VEGF and Ang/Tie pathways hold promise for broader therapeutic applications for AMD than therapies alone. In addition, AMPK has a broad impact on immune cells, which enhances the energy balance of inflammation-associated cells such as T cells, macrophages, and dendritic cells, thus modulating the inflammatory response, protecting injured RPE cells, and preventing AMD development. However, the specific molecular mechanisms that directly contribute to AMD remain unclear and this gap deserves further exploration and research. Therefore, further clarification of the specific link between multiple kinase pathways and the pathogenesis of AMD and investigation of how to expand their therapeutic role is a question that needs to be addressed.

Challenges remain in the clinical translation of kinase inhibitors. These practical challenges are crucial for a comprehensive assessment of the application prospects. For example, the mechanisms underlying Akt2 activation and inhibition remain elusive, and its regulatory role on downstream molecules and compensatory regulation in the context of AMD pathogenesis remain unclear [20]. Due to the complexity of AMD, the unpredictable roles of mTOR pathway feedback regulation and off-target effects in the multifaceted pathology-particularly during long-term rapamycin therapy-a kinome-wide approach to analyze mTOR inhibitor selectivity and potency is probably required [144]. Although the p38 MAPK signaling pathway has recently been identified as a potential target for treating AMD, the specific changes in p38 MAPK phosphorylation in the retina during AMD progression remain to be investigated [33]. In the JAK/STAT signaling pathway, STAT3‘s dual roles in apoptosis and inflammation present challenges for targeted AMD intervention [71, 72, 80, 81]. The dual protective and destructive functions of CaMKII (e.g., retinal exposure to excessive blue light destroys RPE cells) should be clearly understood to guide the identification of appropriate substrates, thereby activating the appropriate signaling pathways to achieve desired clinical treatment outcomes [6]. This review provides a brief summary of the role of multiple kinase pathways in AMD, with the aim of opening new avenues for the prevention and treatment of AMD. Further investigation of kinases and their signaling pathways may prove beneficial, particularly in the context of precision AMD therapy.

Author contributions

Conceptualization: Du YX; Writing—review and editing: Fang JS, Huang Y, Li BW, Du YX. Figures: Huang Y, Li BW, Fang JS. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Natural Foundation of Shandong Province (ZR2024QH579).

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.