SOCS modulates JAK-STAT pathway as a novel target to mediate the occurrence of neuroinflammation: Molecular details and treatment options

SOCS (Suppressor of Cytokine Signalling) proteins are intracellular negative regulators that primarily modulate and inhibit cytokine-mediated signal transduction, playing a crucial role in immune homeostasis and related inflammatory diseases. SOCS act as inhibitors by regulating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, thereby intervening in the pathogenesis of inflammation and autoimmune diseases. Recent studies have also demonstrated their involvement in central immunity and neuroinflammation, showing a dual functionality. However, the specific mechanisms of SOCS in the central nervous system remain unclear. This review thoroughly elucidates the specific mechanisms linking the SOCS-JAK-STAT pathway with the inflammatory manifestations of neurodegenerative diseases. Based on this, it proposes the theory that SOCS proteins can regulate the JAK-STAT pathway and inhibit the occurrence of neuroinflammation. Additionally, this review explores in detail the current therapeutic landscape and potential of targeting SOCS in the brain via the JAK-STAT pathway for neuroinflammation, offering insights into potential targets for the treatment of neurodegenerative diseases.


Introduction
SOCS (Suppressors of Cytokine Signaling) proteins are intracellular negative regulators that were initially discovered in a cDNA library from a monocytic leukemia cell line.They primarily act upon activation by specific cytokines to exert inhibitory effects and disrupt signal transduction (Krebs and Hilton, 2001).Cytokines, as signaling molecules, mediate the body's most fundamental biological processes, such as immunity and hematopoiesis (Linossi et al., 2018).As inhibitors of signal transduction, SOCS proteins play a crucial role in maintaining biological homeostasis.Particularly in immune processes, existing research has demonstrated the involvement of SOCS in various conditions including malignancies (Morris et al., 2018;Chikuma et al., 2017;Yoshimura et al., 2018), rheumatoid arthritis (RA) (Malemud, 2017), systemic lupus erythematosus (SLE) (Tsao et al., 2008), and multiple sclerosis (MS) (Rojas-Morales et al., 2019), where they are recognized as key regulators of immune homeostasis.Moreover, SOCS proteins primarily disrupt inflammatory signaling through multiple pathways including the Janus kinase-signal transducer and activator of transcription (JAK-STAT), NF-kappaB (NF-κB), and transmembrane Toll-like receptors (Yoshimura et al., 2007;Baetz et al., 2004;Durham et al., 2019).Among these, the JAK-STAT pathway is the most classical route through which SOCS exert their immune functions, closely associated with the pathogenesis of inflammation and autoimmune diseases.The inhibitory function of SOCS proteins is CDprimarily derived from their unique central Src homology 2 (SH2) domain and a highly conserved C-terminal SOCS box.The SH2 domain can bind to the receptor tyrosine kinase JAK on the cell surface (Durham et al., 2019), thus limiting receptor stability and the transmission of downstream signaling mechanisms, providing evidence for the classical interpretation of the SOCS-JAK-STAT pathway.SOCS proteins are widely present in various tissue cells, including central nervous cells.Interestingly, only three protein phenotypes-SOCS1, SOCS3, and CIS-are predominantly expressed in the central nervous system, particularly within central glial cells such as microglia, astrocytes, and oligodendrocytes (Yoshimura et al., 2007;Chen and Yao, 2006;Qin et al., 2012).Both SOCS1 and SOCS3 possess a unique kinase inhibitory region (KIR) (Kazi et al., 2014), which can directly inhibit JAK kinase activity.Furthermore, the JAK-STAT pathway is also abnormally activated in neuroinflammatory diseases (Yan et al., 2018), suggesting that SOCS1 and SOCS3 may mediate the occurrence of central neuroinflammation through their interaction with the JAK-STAT signaling pathway in the brain.
Neuroinflammation is a defensive response of the central nervous system to injury and disease; however, uncontrolled excessive responses can trigger neurosystemic diseases (Amanollahi et al., 2023;Leng and Edison, 2021).Current research has identified markers of inflammation and changes in immune cells in the autopsy pathology specimens of patients with various neurosystemic diseases, such as Parkinson's Disease (PD), multiple sclerosis (MS), and stroke (Mass et al., 2017;Wang et al., 2023;Lambertsen et al., 2019;Tansey et al., 2022).Therefore, neuroinflammation may be one of the pathological causes of central nervous system diseases.The occurrence of neuroinflammation is primarily mediated by interactions among neural glial cells within the brain.Microglia, as resident immune cells in the brain, become excessively activated under pathological conditions by injury-related factors, releasing inflammatory cytokines and exhibiting a pro-inflammatory (M1) phenotype bias (Badanjak et al., 2021;Tu et al., 2021).In cases where astrocyte function is impaired, they can exacerbate the activation of microglia by secreting pro-inflammatory mediators (Giovannoni and Quintana, 2020;Linnerbauer et al., 2020), and jointly contribute to the damage of the blood-brain barrier (BBB), inducing the infiltration of peripheral immune cells into the brain and amplifying the immune response, leading to neurotoxicity and ultimately inducing neuronal death.Clearly, strict control of inflammatory responses is a crucial factor in avoiding brain injury, and inhibiting the activation of brain neural glial cells is a potential target to consider.
In summary, the localization (neural glial cells), function, and structural characteristics of brain SOCS protein phenotypes have established a foundational connection with the JAK-STAT inflammatory pathway, offering potential pathways for the inhibition of neuroinflammation.A review of current research on the SOCS-JAK-STAT pathway reveals that studies on the mechanism by which SOCS regulates the JAK-STAT pathway to inhibit inflammation have involved multiple organs and cell types, such as blood, kidneys, skeletal muscles, endothelial cells, the heart, and lungs.However, research in the central nervous system remains limited.Therefore, it is necessary to delve deeper into the relationship between brain SOCS and the JAK-STAT signaling pathway and to thoroughly discuss the feasibility of the SOCS-JAK-STAT pathway as a therapeutic target for neuroinflammation, addressing the gaps in research on the SOCS-JAK-STAT pathway within the brain.

Overview of SOCS protein phenotypes and functions
The SOCS protein family comprises eight encoded proteins including CIS and SOCS1-7, each containing an SH2 domain flanked by variable N-termini and a C-terminal SOCS box (Kazi et al., 2014).The central SH2 domain is the primary area for binding to phosphorylated tyrosine residues on the cell surface and plays a crucial role in inhibiting signal transduction.The variable N-terminal has functional significance (Liang et al., 2014); for instance, SOCS1 and SOCS3 proteins contain a unique short motif at their variable N-terminus known as the KIR, which has the capability to directly inhibit JAK kinase activity.The N-terminal structure of SOCS2 protein is associated with protein stability (Liang et al., 2014;Nicholson and Hilton, 1998), while in SOCS4 and SOCS5 proteins, this region primarily facilitates the recruitment of receptor complexes.The SOCS box motif, consisting of 40 amino acid residues, often serves as a recognition subunit for the ubiquitination mechanism enzymes (ElonginB, ElonginC) dimer and ubiquitin ligase (Cullin5a), responsible for recruiting E3 ubiquitin ligases to form an E3 ubiquitin ligase complex, thereby targeting tyrosine-phosphorylated proteins for ubiquitination (Kile et al., 2002) (Fig. 1).
The structural phenotype of proteins dictates their functional differences.For example, CIS primarily responds to inducers such as erythropoietin, interleukin-3, and growth hormone, interfering with the downstream regulation of the transcription factor STAT5; SOCS2 is mainly induced by growth hormone; and SOCS5 inhibits Th4 differentiation by suppressing interleukin-2 (IL-2) signaling (O'shea and Murray, 2008).In the central nervous system, SOCS1 and SOCS3 proteins can be induced by over thirty different cytokines.Inflammatory cytokines and interferons can induce the overexpression of SOCS proteins to inhibit the activation of immune cells such as microglia and astrocytes (Yoshimura et al., 2018).There are reports of inflammatory stimulants such as thrombin being used to transfect cultures of microglia and astrocytes, resulting in the induction of SOCS protein expression within two hours (Cianciulli et al., 2017).The inflammatory activation of central nervous glial cells is mediated by inflammatory pathways such as JAK-STAT, NF-κB, and TOLL, among which the structural characteristics of SOCS proteins are more significantly related to the actions of JAK kinases.Therefore, the JAK-STAT pathway is often considered the most typical pathway mediated by SOCS and has become an effective route for inhibiting neuroinflammation.

JAK-STAT signaling pathway
The JAK-STAT signaling pathway is one of the primary cytokinemediated signaling pathways, widely expressed within cells and involved in biological processes such as cell proliferation, hematopoiesis, and immunity (Xin et al., 2020).Current research on this pathway is largely focused on immune and cancerous environments.
The JAK-STAT pathway primarily consists of ligands (various extracellular signaling factors), receptors, JAK kinases, and STAT transcription factors.During the activation of the JAK-STAT pathway by ligands, the receptor itself is inactive; it primarily depends on the activation of JAK kinases coupled to the receptor to phosphorylate target proteins forming tyrosine residues, which then recruit and activate STAT transcription factors.The phosphorylated STATs dimerize, and as homodimers or heterodimers, they are transported through the nuclear membrane to regulate the expression of specific genes in the nucleus (Hu et al., 2021;Dodington et al., 2018).
Compared to other signaling pathways, the mechanism of the JAK-STAT pathway is relatively clear; however, the diversity of ligands and the crosstalk with other signaling pathways contribute to the complexity of biological expression (Xin et al., 2020).Particularly in the regulation of inflammation and immunity, the kinase activity of JAK can lead to crosstalk with the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (AKT) pathway (PI3k-AKT), affecting downstream mechanisms (Haftcheshmeh et al., 2022;Elekofehinti et al., 2021).It has been reported that persistent activation of the JAK-STAT signaling pathway is closely associated with many immune and inflammatory diseases (Xin et al., 2020).SOCS, Protein Inhibitors of Activated STAT (PIAS), and Protein Tyrosine Phosphatases (PTP) are the main molecular negative regulators of the JAK-STAT pathway, controlling the signaling transmission of the pathway (Hu et al., 2021).

Specific pathway of SOCS regulation of the JAK-STAT pathway
When extracellular factors bind to receptors in the form of ligands, they induce the phosphorylation of tyrosine residues on the receptor by activating JAK kinases, which are then recruited and bound by STAT for subsequent transport into the nucleus in dimeric form to regulate the expression of specific genes.Currently, the signaling inhibitory function of SOCS proteins is primarily manifested through three pathways (Morris et al., 2018) (i) Pathway of JAK kinase activation inhibition: After cytokine binding to receptors, JAK kinases carrying phosphate are recruited to the JAK activation loop of the signal receptor, completing the phosphorylation of the signal receptor.SOCS proteins can directly inhibit JAK activity by binding to the signal receptor or the JAK activation loop.The SOCS3 protein inhibits JAK kinase recruitment by binding to the receptor, while the SOCS1 protein directly interacts with the JAK activation loop to deactivate it, exerting an inhibitory effect.(ii) Pathway of competition inhibition of tyrosine residue: Under the activation of coupled JAK kinases, the signal receptor phosphorylates target proteins to form tyrosine residues, providing binding sites for STAT transcription factor phosphorylation dimerization.SOCS blocks downstream signal transduction pathways by competitively inhibiting STAT transcription factor tyrosine residue binding sites.CIS competes with STAT5 tyrosine residue docking sites, thereby inhibiting cytokine-induced STAT5 signal transduction and blocking the expression of specific genes in the nucleus.(iii) Pathway of signal receptor degradation: By ubiquitinating tyrosine signaling proteins through E3 ubiquitin ligase complexes in the SOCS box, it directly inhibits receptor signal transduction of cytokines, thereby achieving signal transmission inhibition(Fig.2).

Central nervous system inflammatory response
The central nervous system, as an immune privileged tissue, has a complexity distinct from peripheral immune responses, with only a few types of cells performing immune functions, including the highly specialized macrophages, microglia, which are resident in the brain and play immune functions (Feldman, 2022).In addition, other neuroglial cells in the brain that participate in central nervous system immune responses have been identified, and these cells are believed to mediate neuroinflammation along with microglia, such as extensively studied astrocytes and recently highlighted oligodendrocytes.It has previously been mentioned that SOCS1 and SOCS3 proteins are widely present in the cells of the nervous system, particularly in neuroglial cells, and studies confirm that their expression is mainly induced by inflammatory stimuli, such as inflammatory factors, interferon (IFN-γ), lipopolysaccharides, etc. can be termed as danger-associated molecular patterns (Wu et al., 2021), mainly originating from neuronal damage and peripheral inflammatory infiltration, with glial cells acting as pattern receptors.
Mircolglia are the first line of defence against pathogenic infection in the central nervous system.Pathological reports have confirmed that microglial overactivation is present in the brains of patients with neurodegenerative disorders such as Parkinson's Disease (PD) (Fang et al., 2021)and Alzheimer's Disease (AD) (Sarlus and Heneka, 2017;Cai et al., 2022).In steady states, microglia display a basal level of activity, constantly sensing infection and cellular stress, they can receive danger-associated molecular patterns (such as neurotransmitters, nucleic acids, etc.), and lipopolysaccharides, aggregated proteins, etc., cytokines, and through the JAK-STAT and Toll pathways, mediates cellular phagocytic activity and regulates the production of pro-inflammatory cytokines and chemokines, executing their defensive mechanism (Alhadidi and Shah, 2018).At this time, the intracellular regulatory protein SOCS is largely recruited under the stimulation of inflammatory factors, regulating the transmission of inflammatory signals within microglia.However, prolonged stimulation by danger-associated molecular patterns leads to overactivation of microglia, leading to a phenotypic shift to pro-inflammation, manifested by upregulated expression of inflammatory markers and pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, INF (Banerjee et al., 2017) etc., triggering neuroinflammation.During this time, the expression of SOCS1 and SOCS3 inhibitory proteins and other inflammatory signaling pathways may be the cause of the inflammatory imbalance.Apart from microglia, SOCS protein and JAK-STAT pathway also exist and function in astrocytes (Guillamón-Vivancos et al., 2015;Gao et al., 2022) and oligodendrocytes (Pascual et al., 2021;Xu et al., 2020).Astrocytes can release pro-inflammatory cytokines and chemokines (such as CCL2, CXCL1, CXCL2, CXCL10, GM-CSF, and IL-6), which recruit microglia and simultaneously damage the blood-brain barrier (BBB), and induce the upward infiltration of peripheral T cells and B cells etc., immune cells after receiving inflammatory signals.Following this, the brain's inflammatory response is amplified under the antigen presentation of MHC-I and MHC-II, where MHC-I and MHC-II proteins are able to respectively interact with helper T cells (CD4 + T, CD8 + T) (Gao et al., 2022).It's noteworthy that SOCS is also expressed in peripheral immune cells such as dendritic cells (DC) and T cells.In conclusion, the interaction between peripheral and central immune cells can lead to a cumulative increase of neuroinflammation, which in the end, a persistent neuroinflammatory storm triggers neurotoxicity and causes brain

Neuroinflammation mediated by the SOCS-JAK-STAT pathway
A large body of research data shows that the JAK-STAT signaling pathway is an important mediator for neuroinflammation and immune responses.Various cytokines involved in autoimmune inflammation and immune-related diseases utilize the JAK-STAT pathway for intracellular signal transduction, such as members of the Interleukin (IL)-2 family (IL-2, IL-7, etc.), IL-6 family members (IL-6, IL-10) and IFN-γ cytokines.Among them, IFN-γ and IL-6, as the two most effective activators in the JAK-STAT pathway, are elevated in neuroinflammatory Parkinson's Disease (Yan et al., 2018).Furthermore, a study that treated a rat model of Parkinson's Disease with the JAK-STAT pathway inhibitor AZD1480 found a reduction in microglia, decreased expression of MHC-II, and a decrease in the levels of pro-inflammatory cytokines produced by activated microglia four weeks post-transfection (Qin et al., 2016).Recent studies have shown that by enhancing the expression of the triggering receptor expressed on myeloid cells 2 (TREM2), the activation phosphorylation process of JAK2 and STAT3 can be effectively inhibited.This mechanism promotes the transformation of microglial phenotype from M1 type to anti-inflammatory M2 type, and simultaneously reduces the synthesis and release of inflammatory factors (Hu et al., 2012).In addition, under the stimulation of lipopolysaccharides, down-regulating the JAK-STAT signaling pathway can significantly reduce the amount of pro-inflammatory mediators such as TNF-α and IL-1β secreted by microglia (Shrivastava et al., 2013).
These findings suggest that the JAK-STAT pathway is a major conduit for mediating neuroinflammation, and SOCS, as a regulatory factor of the JAK-STAT pathway, also plays a negative feedback role in the brain, affecting the occurrence of neuroinflammatory diseases.This view has been confirmed by the following research: Kiran Kundu et al. found that the Japanese encephalitis virus can regulate the expression of cytokine signaling (SOCS) 1 and 3 in macrophages, causing changes in the JAK-STAT signaling cascade, thereby inhibiting the release of proinflammatory cells and chemokines (Kundu et al., 2013).John Bosco Ruganzu confirmed that overexpression of the triggering receptor on myeloid cells-2 (TREM2) expressed on myeloid cells can reduce neuroinflammation through the SOCS-JAK-STAT signaling pathway, thus saving cognitive deficits in mice (Ruganzu et al., 2021).SOCS3 is a negative regulator of STAT3, capable of inhibiting signal transduction of the IL-6 cytokine family and interfering with the migration of immune cells in the central nervous system (Doti et al., 2012).Researchers such as Dominguez used lentiviral technology to specifically induce the expression of SOCS3 protein, successfully achieving selective shutdown of the JAK/STAT3 signaling pathway in central immune cells-microglia (Lofrumento et al., 2014).Additionally, upregulated expression of SOCS1 by resveratrol has been found to significantly reduce neuroglial activation and levels of pro-inflammatory cytokines, supporting a possible protective role for SOCS1 in neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Dominguez et al., 2010).By using recombinant SOCS proteins or adenovirus vectors that express SOCS, upregulated expression of SOCS proteins has been achieved, thereby improving the progression of inflammatory neurodegenerative diseases (Petzinger et al., 2015).However, the regulatory mechanisms of SOCS proteins are extremely complex, and their overexpression could negatively impact normal immune responses in certain circumstances.For example, enhancing cytokine signaling by siRNA or dominant-negative SOCS protein expression to downregulate SOCS genes could help to strengthen anti-tumor or anti-viral immune responses.In summary, this review demonstrates the feasibility of SOCS in regulating the JAK-STAT pathway and its association with glial cells, along with viable targets for neuroinflammatory diseases (Table 1)

Parkinson's disease
Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, with the hallmark pathologies being the selective degeneration of dopaminergic neurons in the pars compacta of the substantia nigra (SNpc) and Lewy body (LB) formation (Petzinger et al., 2015;Tolosa et al., 2021).The causes of the disease are largely genetic, with some sporadic cases observed.In recent years, both neuropathological and neuroimaging studies have supported the existence of continuous and terminal neuroinflammatory processes in patients with PD (Pajares et al., 2020).Numerous experiments from humans and animals have likewise confirmed the presence of neuroinflammation in PD.For instance, pathologic reports have identified over-activation of microglial cells in the brains of PD patients (Badanjak et al., 2021;Kam et al., 2020).Thus, neuroinflammation has become one of the focal points in the exploration of PD pathogenesis.Accordingly, the inflammatory activation pathways of microglial cells have been identified as effective routes towards improving PD.
To investigate the application of the SOCS-JAK-STAT pathway in PD, studies have confirmed the presence of JAK kinase on the surface of microglial cells.It was found that under the stimulation of cytokines such as inflammatory factors, JAK kinase activates STAT to express inflammatory mediators, leading to a pro-inflammatory bias in microglial cells (Yan et al., 2018).This provides the basis for the occurrence of the SOCS-JAK-STAT inflammatory pathway in microglial cells.In addition, studies have found that activators of the JAK-STAT pathway are elevated in PD.Experiments have reduced the expression of MHC-II class and inflammatory genes in PD mice through a JAK-STAT inhibitor (AZD1480).Studies using aggregated α-Syn to stimulate mouse microglial cell line resulted in the expression of MHC-II class and the production of NO, TNF-α, and IL-1β.After adding the JAK1/2 inhibitor (AZD1480), this response was eliminated.These experiments all point to the same result -that the SOCS-JAK-STAT mediates the occurrence of neuroinflammation, affecting the progression of PD.Therefore, targeting the JAK-STAT pathway is a new hope for inhibiting Parkinson's disease.
At present, research on improving Parkinson's disease (PD) through the SOCS-JAK-STAT pathway is mainly focused on the inhibition of the JAK-STAT pathway.Considering maturity, current research on inhibitors of SOCS protein is still lacking, only in non-human experiments using gene knockout and RNA interference technology to confirm the inhibitory effect on neuroinflammation.For example, studies by SHEN L (Shen et al., 2004) and others using gene silencing technology for SOCS1 have demonstrated the effect of SOCS protein on the biological  et al., 2010) characteristics and functions of human dendritic cells.Furthermore, Md Gulam Musawwir Khan (Khan et al., 2023) and others have achieved regulation of the immune response to antigens on the surface of dendritic cells in hepatocellular carcinoma patients by silencing SOCS1.Additionally, Zhang Shuying and others have regulated the proliferation of oral carcinoma KB cells by silencing SOCS1 gene expression.These successful studies, reflected in different diseases, provide valuable reference for the application of gene silencing technology.

Alzheimer's disease
Alzheimer's disease (AD) is a chronic progressive neurological disorder, also known as senile dementia.Deposition of amyloid-beta protein and accumulation of tau protein isolated from the brains of AD patients during autopsy are the main pathological features (Hane et al., 2017), but its pathogenesis is complex.In recent years, new evidence suggests that neuroinflammation may be one of the pathogenic mechanisms of AD (Leng and Edison, 2021;Rajesh and Kanneganti, 2022).For example, neuroglial cells in the brain, neutrophils, and peripheral macrophages collectively mediate neuroinflammation in AD (Al-Ghraiybah et al., 2022).The presence of the JAK-STAT signaling pathway within neuroglial cells (astrocytes and microglia) promotes the transmission of neuroinflammatory signals.Genome-wide association studies also indicate a close association between JAK-STAT signaling and AD, which may be related to the inflammatory process of AD.Therefore, inhibiting the JAK-STAT pathway to limit neuroinflammatory responses may be a potential therapeutic target for treating AD progression.Numerous studies have confirmed the positive role of the SOCS-JAK-STAT pathway in this regard.Ischemia in the brain's vascular system may trigger the deposition of amyloid peptides, leading to the development of AD, known as the ischemic theory of AD.Studies have found that after cerebral ischemia, there is dysregulation of JAK-STAT signal transduction, and successful inhibition of brain ischemic injury effects was achieved using JAK2-STAT3 pathway inhibitor AG490 (Yu and Li, 2020;Fan and Zhou, 2021).
Numerous studies have obtained positive results in suppressing neuroinflammation by targeting the inhibition of the SOCS-JAK-STAT pathway.For instance, the use of the JAK2-STAT3 inhibitor AG490 leads to the phosphorylation of JAK2 and inhibition of STAT3, with a noted reversal in the symptom scoring tests of DA patients (Müller et al., 1993).Chiba et al (Chiba et al., 2009).also pointed out that the phosphorylated (p) or active form of STAT3 (p-STAT3) is significantly reduced in the hippocampal neurons of AD patients, establishing the deactivation of STAT3 as relevant to the inflammatory pathogenesis of AD.After silencing the gene expression of STAT3 in microglia using siRNA technology, a mitigation of the oxidative stress response induced by beta-amyloid oligomers was observed, specifically reflected in the reduced release of reactive oxygen species and NO within cells (Wang et al., 2017).In summary, these findings demonstrate the efficacy of SOCS in regulating the JAK-STAT pathway to inhibit the occurrence of neuroinflammation in AD.

Multiple sclerosis
Multiple Sclerosis (MS) is also a recurrent neurodegenerative disease characterized primarily by demyelination of the brain and loss of oligodendrocytes.Pathological studies have identified autoimmunity as one of its principal pathogenic mechanisms (Correale et al., 2017;Dendrou et al., 2015), and clinical improvements in MS and its recurrence rate have been achieved through immunomodulation.Autoreactive cells such as CD4 + T cells, CD8 + T cells, B cells, and bone marrow cells have been proven to trigger the onset of the disease (Dendrou et al., 2015).Microglia and peripheral infiltrating macrophages have also been found in the central nervous system during the onset of MS.Astrocytes have been shown to be activated by the JAK-STAT signaling pathway during the disease, releasing various soluble mediators that activate immune cells and recruit them to the central nervous system, exacerbating the inflammatory response (Guillamón-Vivancos et al., 2015).Additionally, studies have confirmed that dysregulation of CD4 + T cells, dependent on the JAK-STAT pathway, is associated with the pathogenesis of MS (Korn and Kallies, 2017), and the overexpression of SOCS1 can inhibit the activation of STAT1 induced by IFN-γ, leading to a reduction in MS-related CD4 + T cells; research has observed that SOCS1 protein mimicking tyrosine kinase inhibitor peptide (Tkip) can regulate the disease progression in an MS animal model by interacting with autophosphorylated JAK2 (Vogel et al., 2013).In summary, it is feasible that SOCS proteins can treat Multiple Sclerosis through the JAK-STAT signaling pathway.(Table 2)

Therapeutic prospects of the SOCS-JAK-STAT pathway in neuroinflammation
Targeting the SOCS-JAK-STAT signaling pathway holds promise as a treatment option for neurodegenerative diseases, brain tumors, and other disorders.The discovery of SOCS regulation of the JAK-STAT pathway and targeted therapy can effectively restrain the aggravation of neuroinflammation, thus preventing the further development of inflammation-related diseases.Existing research has confirmed, for instance, that upregulating the expression of SOCS1 and SOCS3 promotes the transition of macrophages from M1 to M2 via the JAK-STAT pathway (Banerjee et al., 2017;Pascual et al., 2021).A deeper understanding of the role of the SOCS-JAK-STAT pathway in neuroinflammation can enrich the network of neuroinflammation suppression, advance the development of treatment methods for neurodegenerative diseases, and enhance the therapeutic effect on neuroinflammatory diseases.However, there are also potential risks associated with SOCS therapy.For example, studies have shown that an increase in SOCS3 expression may weaken antiviral activity and affect the immune system's response efficiency to viruses such as HIV (La Manna et al., 2021).Therefore, it is important to carefully consider this dual action of SOCS and individual variability when making rational choices in treatment strategies.When designing personalized medical plans, it is necessary to fully take into account the patient's specific conditions and needs to ensure the safety and effectiveness of treatment.
Given the overwhelming evidence suggesting that targeting the SOCS-JAK-STAT pathway can regulate neuroinflammation, it is hoped that this pathway will be a new trend in treating neuroinflammation in the future.The development of anti-inflammatory drugs is no longer surprising, but the current focus of drug development is on inhibiting the JAK-STAT pathway, such as JAK inhibitors like Tofacitinib and Baricitinib (Gooderham et al., 2019).However, drug development targeting SOCS is not yet ideal, and apart from natural extracts such as curcumin, resveratrol, and oleanolic acid, the future research will most likely emphasize on developing drugs to regulate SOCS.We cannot ignore that drug treatments come with certain side effects, so exercise therapy as a non-drug prescription can also be a potential approach.Some studies have found that exercise can regulate the SOCS-JAK-STAT signals in various organs and cells, though the most appropriate exercise intensity and frequency still need to be explored.Additionally, given the multiple subtypes of SOCS proteins and their complex mechanisms of action, future studies may focus on exploring the roles of different specific subtypes through in vitro experiments and animal models.The regulatory mechanism of SOCS proteins is extremely complex, and their overexpression may negatively affect normal immune responses in certain cases.For instance, some studies have enhanced anti-tumor or anti-viral immune responses by down-regulating the SOCS genes through siRNA.Therefore, analyzing the dual roles of SOCS under different pathological states will also be crucial in future studies.

Therapeutic methods and current status targeting the SOCS-JAK-STAT signaling pathway
Currently, the therapeutic strategies focused on the suppression of neuroinflammation through the SOCS-JAK-STAT signaling pathway predominantly involve the regulation of SOCS protein expression and the direct inhibition of key molecules in the JAK-STAT pathway.Existing treatments include SOCS mimetic peptides and antagonists (Flowers et al., 2004), clinical drug interventions (Pandey et al., 2023), exercise therapy (Almeida-Oliveira et al., 2019), and natural products (Porro et al., 2019).These methods have been partially validated in animal models or clinical trials.

SOCS mimetic peptides and antagonist
In recent years, scientists and medical professionals have been working to design and apply this method in clinical interventions, aiming to target the JAK-STAT pathway with innovative approaches, and to create mimetics and antagonists that target SOCS.Some studies have successfully designed small molecule tyrosine kinase inhibitory peptides (TKIP) (Pandey et al., 2023), which have been developed as SOCS protein mimetics, effectively inhibiting JAK2-mediated STAT1 phosphorylation.SOCS-KIR, as a unique mimetic peptide, bears natural similarity to SOCS, and possesses advantages such as small size and good stability (La Manna et al., 2021).Therefore, combining SOCS protein mimetics with drug delivery systems can be utilized for the treatment of inflammatory diseases.SOCS mimetics and antagonists hold promise as potential therapies to modulate the immune system.They can regulate the immune system in both inhibitory and stimulatory manners, becoming safe and effective therapeutic candidates.

Clinical trial drug
Presently, the development of clinical drugs targeting the SOCS-JAK-STAT pathway is continuously progressing.Some drugs have already been approved by the FDA, such as Tofacitinib (Hashimoto et al., 2019), an oral JAK inhibitor.There are also some inhibitors in clinical trials, such as the SOCS protein inhibitor CSG112 (Cyclosporin A), CNI-101, the JAK inhibitor Baricitinib, and the STAT inhibitor Ruxolitinib (Gooderham et al., 2019).The continuous development of these drugs is pushing forward the advancement of treatments related to the SOCS-JAK-STAT pathway, and hopefully providing new treatment options for various inflammatory diseases and cancers.However, the use of these drugs should follow the doctor's instructions and clinical trial results.

Exercise intervention
Non-pharmacological exercise therapy has emerged as an alternative therapy in recent years.Studies have shown that aerobic exercise upregulates the expression of SOCS, inhibits microglial cell activation through the JAK-STAT pathway, and thereby suppresses neuroinflammation and loss of dopaminergic neurons (Yang et al., 2016).Moderate exercise not only activates the JAK-STAT pathway, thereby upregulating the expression of certain anti-inflammatory cytokines (IL-10), but also lowers the levels of pro-inflammatory cytokines (TNF-α, IL-6) (Soraci et al., 2023).Currently, there is relatively limited research on exercise intervention in the SOCS-JAK-STAT pathway, but the effects of exercise on the immune system are multifaceted, including regulation of cytokine production and improvement of immune cell function.Therefore, exercise has a certain therapeutic potential.However, it is important to note that while exercise may have potential regulatory effects on the SOCS-JAK-STAT pathway, the specific mechanisms still require further study.
Furthermore, the benefits of exercise depend on various factors, including the type, intensity, duration, and frequency of exercise, as well as individual health status and genetic background.Future research may delve deeper into how exercise can most effectively intervene in the SOCS-JAK-STAT pathway under what conditions, to promote immune health and prevent disease.

Natural products
In recent years, a significant amount of research has characterized the key role that natural extracts play in the inhibition of the SOCS-JAK-STAT pathway, such as curcumin (Porro et al., 2019), resveratrol, and ursolic acid (Song et al., 2021).Curcumin has been proven to upregulate the expression of SOCS1 and SOCS3.Clinical data show that consuming curcumin from the diet can enhance neurogenesis.Resveratrol directly targets inflammatory factor signals, inhibiting the SOCS-JAK-STAT mediated inflammation pathway from the source.This suggests that natural extracts are a viable approach for inhibiting the onset of neuroinflammation and preventing neurological diseases.Additionally, studies have proposed that traditional Chinese medicine plays a role within the SOCS-JAK-STAT pathway.For instance, ginseng saponin reduces phosphorylation of JAK1, STAT1, STAT3, and decreases the expression of inducible nitric oxide synthase (iNOS).This inhibits the proliferation of BV2 microglia cells, alleviating the inflammatory response (Song et al., 2023).It should be noted that prior to using these natural products as medication or therapy, rigorous clinical trials and evaluations should be conducted.Furthermore, due to the complex The level of oxidative stress in microglia caused by β-amyloid white oligomer was weakened, and the release of reactive oxygen species and NO in fine cells was reduced (Müller et al., 1993) Multiple Sclerosis

Microglia Activation of JAK2
The activation of microglia is induced or indirectly induced, and the expression of pro-inflammatory factors IL-1 and IL-6 is increased, thereby affecting the progression of AD Modulates disease progression in an MS animal model of sclerosis by identifying autophosphorylated JAK2 interactions (Dendrou et al., 2015) M. Yan et al. components of natural products, products of different origins and purities may have different biological activities.Therefore, quality control and standardization issues need particular attention in research and application.

Challenges and future direction
With the progression in the field of neurodegenerative diseases, the suppression of neuroinflammation and the resultant improvement of the overall immune microenvironment has emerged as a key strategy for treating neurodegenerative conditions.Consequently, targeting SOCS combined with the JAK-STAT signaling pathway as a therapeutic approach for neuroinflammation poses several challenges.One of the primary concerns is disease factors; under varying disease states such as autoimmune diseases (Liang et al., 2014), trauma (Tsai et al., 2011), brain ischemia, tumors, and viral or bacterial infections (Koga et al., 2009), aberrations in the expression and functionalities of SOCS proteins may occur.The complexity and interactivity of the immune response may cause SOCS proteins to antagonize inhibitory cytokine-mediated JAK-STAT pathways in their negative feedback regulation, leading to inhibitory cross-talk.Furthermore, genetic predisposition, aging, and environmental elements could also pose risks and challenges to this pathway.To safeguard the SOCS-JAK-STAT signaling axis, maintaining healthy dietary practices and regular physical activity are beneficial in supporting the normal functionality of SOCS proteins, in addition to pharmacological interventions.Although the field faces certain challenges, clinical research suggests that modulating the SOCS-regulated JAK-STAT pathway to mitigate neuroinflammation could potentially delay the progression of neuroinflammation and related neurological diseases.
In summary, this review addresses the onset of neuroinflammation by proposing the potential role of SOCS proteins in modulating the JAK-STAT signaling pathway to inhibit neuroinflammation.It also delineates the molecular intricacies of this regulatory mechanism.Moreover, the article reviews the latest research advancements in treating neuroinflammatory diseases through targeting the SOCS-JAK-STAT pathway, providing new therapeutic strategies and research directions in the domain.However, this review has certain limitations: firstly, discussions on the molecular details of SOCS proteins within the brain are not comprehensive, as research tends to focus on the SOCS1 and SOCS3 subtypes while studies on other SOCS4-SOCS7 are limited; secondly, the intricate interactions and cross-talk mechanisms between various cytokines and SOCS proteins that regulate the JAK-STAT pathway have not been thoroughly explored within this review.Lastly, although positive/ negative regulatory therapeutic strategies targeting SOCS have shown some success in rodent models, the limitations inherent in experimental methodologies and models might not fully reflect human physiology, which could affect the general applicability of research findings.Therefore, there is a compelling need for more holistic, safer, and more effective inhibition strategies targeting the SOCS-JAK-STAT inflammatory pathway due to its vast potential and necessity.

Fig. 1 .
Fig. 1.Composition and structure of SOCS proteins.The SOCS protein family consists of eight encoded proteins: CIS, SOCS1-7.Each protein contains a central Src homology 2 (SH2) domain, as well as variable N-terminal and SOCS box C-terminal domains.The central SH2 domain is the primary region that interacts with phosphorylated tyrosine residues on the cell surface, and it is involved in the inhibition of cell signaling.The variable N-terminal domain has functional relevance, while the SOCS box motif is composed of 40 amino acid modules.It often acts as a recognition subunit for the ubiquitination machinery enzymes (ElonginB, ElonginC) and the ubiquitin ligase (Cullin5a), responsible for recruiting E3 ubiquitin ligases to form E3 ubiquitin ligase complexes.This facilitates the ubiquitination of target proteins, particularly those phosphorylated on tyrosine residues.

Fig. 2 .
Fig. 2. Regulation of the JAK-STAT signaling pathway by SOCS.There are three mechanisms by which SOCS proteins exert their signaling inhibitory functions: (i) inhibition of JAK kinase activation, (ii) competition for tyrosine residues, and (iii) degradation of signaling receptors.

Table 2
The Role of SOCS-JAK-STAT Pathway in Neuroinflammatory Diseases.