Посттрансляционные изменения в нейроиммунных клетках во время нейроинфламмации: комплексные сети регулирования и терапевтические возможности.

Introduction

Neuroinflammation constitutes a complex immune response within the CNS that arises in response to a variety of pathological stimuli, such as infections, traumatic injury, ischemia, exposure to neurotoxic agents, and autoimmune challenges. This intricate process entails the activation of resident immune cells, including microglia, astrocytes, and oligodendrocytes, alongside the release of a diverse array of inflammatory mediators. Moreover, neuroinflammation frequently compromises the structural and functional integrity of the BBB, thereby facilitating the infiltration of peripheral immune cells and amplifying inflammatory cascades [ 1 ]. While a properly regulated inflammatory response is crucial for pathogen clearance and tissue repair, excessive or chronic neuroinflammation has detrimental effects and is strongly implicated in the pathogenesis and progression of various CNS disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), ischemic stroke (IS), and traumatic brain injury (TBI) [ 1 – 3 ].

PTMs are covalent, typically enzymatic alterations that occur on proteins subsequent to translation, significantly impacting protein conformation, stability, subcellular localization, interaction networks, and degradation pathways. PTMs represent a crucial regulatory mechanism for cellular processes and signaling pathways. Traditional PTMs, such as ubiquitination, SUMOylation, phosphorylation, acetylation, methylation, and glycosylation, have been extensively investigated and are recognized for their role in modulating a wide array of biological functions [ 4 , 5 ]. In addition to these well-characterized modifications, a growing body of evidence underscores the role of newly identified PTMs—including redox-based modifications, succinylation, and lactylation—in the regulation of neuroinflammatory responses [ 6 – 8 ].

The complex interaction between PTMs and neuroinflammation has become a central theme in contemporary neuroscience research. PTMs function as dynamic molecular switches that precisely regulate immune cell activation, control the secretion of inflammatory cytokines, and influence the activity of critical signaling pathways, thereby shaping the progression of CNS pathologies. Recent research has provided substantial evidence that abnormal PTMs play a significant role in the onset and advancement of neurodegenerative diseases. For example, the hyperphosphorylation and dysregulated ubiquitination of the microtubule-associated protein Tau are characteristic pathological features of Alzheimer’s disease (AD) and related tauopathies, highlighting the pathological significance of PTM imbalances in CNS disorders [ 9 ]. Collectively, these findings emphasize the need for a deeper mechanistic understanding of PTM-mediated regulatory networks in neuroinflammation, which could facilitate the development of novel diagnostic biomarkers and targeted therapeutic strategies for CNS diseases.

Microglia

Microglia, the intrinsic immune cells of the central nervous system, play dual roles in preserving neural homeostasis and responding to pathological challenges. For analytical purposes, they are frequently classified into M1-like or M2-like states, which generally correspond to pro-inflammatory and anti-inflammatory functional orientations, respectively [ 10 ]. PTMs are regarded as critical modulators that influence microglial polarization by altering neuroinflammation-related signaling pathways or key molecular mediators. This modulation determines their differentiation trajectory and functional outcomes, either in promoting inflammation or facilitating tissue repair [ 11 ]. Although the majority of research has predominantly focused on macrophages or tumor-associated macrophages, these findings may offer valuable insights into the regulatory mechanisms of PTMs in microglia.

Phosphorylation

Phosphorylation represents a crucial mechanism of signal transduction in microglia, modulating cellular processes by the addition of phosphate groups to specific amino acid residues—serine, threonine, or tyrosine—thereby activating or inhibiting downstream responses [ 12 ]. Kinases modulate the physiological state of microglia by altering the conformation, subcellular localization, and binding affinities of target proteins, thereby initiating or terminating signaling cascades [ 13 ]. This regulatory mechanism is particularly significant in the context of microglial immunosurveillance and inflammatory responses.

Within pro-inflammatory pathways, the p38α mitogen-activated protein kinase (MAPK) functions as a pivotal node. Exogenous stimuli, such as lipopolysaccharide (LPS) or β-amyloid, activate Toll-like receptors (TLRs), leading to the phosphorylation and activation of p38α. Once activated, p38α phosphorylates the transcription factors ATF2 and ELK1, facilitating their translocation to the nucleus and subsequent binding to the promoters of inflammatory genes, including interleukin-1β (IL-1β), TNF-α, and interleukin-6 (IL-6), thus promoting cytokine transcription [ 14 , 15 ]. Genetic deletion or pharmacological inhibition of p38α results in a reduction in the production of these mediators and alleviates neuronal synaptic loss and morphological degeneration [ 16 ]. In addition to its role in inflammation, p38α is involved in the maintenance of microglial homeostasis. During the process of autophagy, p38α phosphorylates ULK1 (UNC51-like kinase 1), leading to the suppression of ULK1 activity and disrupting its interaction with ATG13. This disruption inhibits the assembly of the autophagy initiation complex, thereby reducing autophagic flux [ 17 ]. Consequently, p38α-dependent phosphorylation not only enhances the expression of inflammatory genes but also exacerbates microglial pro-inflammatory states by hindering homeostatic processes such as autophagy.

Similarly, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway functions as a pivotal axis in microglial inflammatory signaling. Cytokines such as interferon-γ (IFN-γ) and IL-6 activate receptor-associated JAK1 and JAK2, which in turn phosphorylate STAT1 and STAT3 [ 18 , 19 ]. The phosphorylated STATs dimerize, translocate to the nucleus, and bind to gamma-activated sequence (GAS) or interferon-stimulated response elements (ISRE) to initiate the transcription of pro-inflammatory genes, including iNOS, TNF-α, and IL-1β [ 20 ] (Fig. 1 ). In models involving the combined stimulation of IFN-γ and LPS, the degree of STAT1 phosphorylation is positively correlated with the expression of NLRP3 inflammasome-associated effectors, such as caspase-1 and gasdermin D [ 19 ]. The inhibition of STAT1 phosphorylation, through pharmacological agents like fludarabine or via genetic deletion of STAT1, results in a reduction in the upregulation of these inflammatory molecules and mitigates the pro-inflammatory phenotype of microglia [ 18 ]. The suppressor of cytokine signaling (SOCS) family provides negative feedback. Induced in response to neural injury or infection, SOCS proteins modulate JAK/STAT signaling by binding to receptors or JAKs to inhibit tyrosine kinase activity and by facilitating the ubiquitin-mediated degradation of pathway components [ 21 ]. This regulation limits sustained STAT phosphorylation and attenuates inflammation [ 22 , 23 ].

Ubiquitination

While phosphorylation and ubiquitination functionally intersect in microglia, their primary mechanisms and outcomes remain distinct. Phosphorylation rapidly modulates protein activity, propagating or terminating signaling pathways, and often directly influences transcription factors or the autophagy machinery. In contrast, ubiquitination primarily alters protein stability, trafficking, and complex assembly through chain type-dependent signals, thereby regulating the intensity and duration of immune responses [ 24 ]. Collectively, these modifications orchestrate both the magnitude and persistence of microglial inflammatory programs.

Ubiquitination is a highly regulated enzymatic cascade involving the coordinated actions of the E1 activating enzyme, E2 conjugating enzymes, and E3 ligases, which collectively ensure the precise modification of selected substrate proteins. By covalently attaching ubiquitin to lysine residues or the N terminus of target proteins, this process encodes distinct signaling outcomes [ 25 ]. In microglia, the primary types of ubiquitin linkages are K48, Lysine 63-linked ubiquitin chain (K63), and M1. Within the TLR4 signaling pathway, TRAF6 associates with the E2 complex Ubc13 and Uev1A to form K63-linked ubiquitin chains. These chains are recognized by TAB2 or TAB3, facilitating the activation of TAK1 and establishing a scaffold for subsequent signaling processes [ 26 , 27 ]. Pellino1 and Pellino2 can either collaborate with or, in specific contexts, replace TRAF6 to generate K63 chains, thereby enhancing and stabilizing inflammatory signaling [ 25 ] (Fig. 1 ). Through these K63 linkages, TRAF6, Pellino1, and Pellino2 drive the activation of the TAK1 pathway [ 28 , 29 ]. Subsequently, TAK1 activates the IκB kinase (IKK) complex, thereby propagating NF-κB signaling, which is a pivotal step in the MAP kinase and NF-κB signaling cascades [ 30 ].

M1, or linear ubiquitin chains, are synthesized by the Linear ubiquitin chain assembly complex (LUBAC) complex and bind to the NEMO (IKKγ) subunit of the IKK complex, thus facilitating TAK1-dependent IKK activation while functioning independently of the MAP kinase pathway [ 31 ]. The UBAN domain of NEMO exhibits a high affinity for both M1 and K63 linkages, which frequently occur as mixed or colocalized chains to form robust signaling scaffolds. Recent studies have demonstrated that linear ubiquitination can facilitate the liquid-liquid phase separation of NEMO, thereby spatially concentrating IKK components and enhancing activation efficiency [ 32 ]. In microglia, TRAF6 plays a particularly crucial role, serving as a core E3 ligase for K63-linked ubiquitin chains and recruiting LUBAC to form composite K63 and M1 ubiquitin architectures. These architectures enhance both the magnitude and duration of NF-κB signaling [ 33 ]. This scaffolded signaling pathway predisposes microglia to adopt a predominantly pro-inflammatory M1-like phenotype, leading to increased secretion of pro-inflammatory mediators such as TNF-α and IL-1β (Fig. 1 ). Additionally, Pellino1 promotes K63 ubiquitination of TRAF6, thereby activating both the MAPK and NF-κB pathways [ 34 ]. Counter-regulation is mediated by deubiquitinating enzymes that remove or edit ubiquitin chains to mitigate excessive inflammatory responses. The RNF11 and A20 editing complex can trim K63 chains and redirect substrates towards K48-linked proteasomal degradation, thereby attenuating NF-κB activity [ 35 , 36 ]. OTULIN specifically hydrolyzes M1-linked ubiquitin chains, whereas Cylindromatosis tumor suppressor protein (CYLD) preferentially removes K63-linked chains and a subset of M1 linkages. In conjunction with A20, these deubiquitinating enzymes (DUBs) exert multiple regulatory constraints on the NEMO and TAK1-IKK signaling pathway, thereby preventing excessive signaling and aiding in the resolution of inflammation [ 37 , 38 ].

SOCS proteins introduce an additional regulatory layer. Their Src homology 2 (SH2) domains specifically recognize phosphotyrosines to mitigate intracellular signaling [ 39 ], while their SOCS boxes facilitate the recruitment of E3 ubiquitin ligase complexes that ubiquitinate phosphorylated receptors or adaptor proteins [ 40 ]. E3 ligases play a pivotal role in determining the type of ubiquitin chain and the subsequent fate of the signal. The specific interaction between E3 ligases and E2 conjugating enzymes dictates the selection of ubiquitin linkage. RING-type E3 ligases, such as TRAF6, in association with Ubc13 and Uev1A, preferentially promote K63-linked ubiquitin chain extension, thereby enhancing signal amplification and scaffold formation [ 41 ]. Cellular inhibitor of apoptosis proteins (cIAPs) can also facilitate the assembly of combined K63 and M1 ubiquitin chains, further augmenting pro-inflammatory responses [ 42 ]. Importantly, Membrane-associated RING-CH protein 2 (MARCH2) is capable of directly attaching K48-linked ubiquitin chains to NEMO, leading to its degradation and thus serving as a molecular switch between linear or scaffold-driven signal amplification and K48-mediated protein clearance [ 43 ] (Fig. 1 ).

Acetylation

In microglia, acetylation modifies lysine residues, thereby altering protein charge, conformation, and interactions with DNA or partner proteins. This process influences chromatin remodeling, transcriptional regulation, signal transduction, and metabolic processes [ 44 ]. Upon pro-inflammatory stimulation, agents such as LPS and IFN-γ induce acetylation at specific histone sites, including H3K9, H3K27, and H4K16. This modification reduces histone-DNA affinity, leading to chromatin relaxation and increased promoter accessibility for inflammatory genes such as inducible nitric oxide synthase (iNOS), TNF-α, and IL-1β [ 45 , 46 ]. Acetylation also synergizes with transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1) to enhance their binding and promote gene activation [ 47 ]. Conversely, histone deacetylases (HDACs) and the NAD + -dependent deacetylase Sirtuin 1 (SIRT1) remove acetyl groups, resulting in chromatin compaction and repression of pro-inflammatory pathways [ 48 ]. In alignment with this framework, inflammatory stimuli rapidly increase H3K27ac and H3K9ac levels and recruit histone acetyltransferases (HATs) such as p300/CBP to inflammatory promoters, while HDAC activity counteracts these modifications [ 49 , 50 ]; These mechanisms have been substantiated in microglia and related immune cell models (Fig. 1 ).

In addition to histones, non-histone acetylation plays a crucial role in the regulation of microglial activity. Specifically, the acetylation of the NF-κB p65 (RelA) subunit enhances its DNA binding affinity, transactivation potential, and nuclear retention, thereby intensifying inflammatory signaling. Conversely, SIRT1-mediated deacetylation attenuates p65 activity and its associated transcriptional program [ 51 ]. Similarly, acetylation of p53 at lysine 379 augments its stability and facilitates the expression of genes associated with inflammation; SIRT1 activation leads to deacetylation at this site, thereby mitigating excessive microglial activation [ 52 ]. Mechanistically, p300/CBP/GCN5 directly acetylate p65, enhancing transcriptional output, whereas SIRT1 and specific HDACs deacetylate p65 and p53, exerting negative regulatory control (Fig. 1 ). Collectively, these opposing processes function as a regulatory switch that modulates microglial inflammatory versus pro-resolving responses [ 53 ] (Fig. 1 ), with consistent anti-inflammatory effects observed in models of central nervous system inflammation and retinal injury [ 54 ].

Acetylation is intricately linked to cellular metabolism, with acetyl-CoA, the acetyl donor, being regulated by glycolysis, fatty-acid oxidation, and oxidative phosphorylation [ 55 ]. During metabolic reprogramming, acetylation levels closely follow the dynamics of acetyl-CoA, thereby influencing microglial inflammatory responses and phagocytic behavior. Recent studies indicate that the metabolically sensitive histone acetyltransferase (HAT) GCN5 serves as a critical link between nutrient availability and the acetylation of both histone and non-histone proteins, thereby modulating inflammatory transcriptional profiles. Furthermore, the establishment of trained innate immune memory is contingent upon metabolism-driven acetylation reprogramming [ 53 , 56 , 57 ]. In models of retinal neuroinjury, the activation of SIRT1 has been shown to suppress microglial overactivation and excessive synaptic engulfment, highlighting the translational potential of modulating acetylation through the interplay of metabolism and epigenetics [ 54 ].

Overall, acetylation operates through reversible modifications of histone and non-histone proteins and is precisely regulated by the coupling of metabolic and epigenetic mechanisms via acetyl-CoA availability. This intricate regulation collectively influences chromatin accessibility and the activity of key transcription factors in microglia, thereby modulating microglial reactivity across inflammatory, homeostatic, and pro-resolving states.

SUMOylation

SUMOylation, as a highly dynamic PTM, plays a pivotal role in modulating microglial responses during neuroinflammation. This stress-responsive modification swiftly engages with numerous substrates to alter cellular signaling pathways and mitigate excessive inflammatory activation, thereby maintaining tissue homeostasis [ 58 ]. Small ubiquitin-like modifiers (SUMOs), which include SUMO1, SUMO2, SUMO3, SUMO4, and SUMO5 in mammals, covalently bind to lysine residues on target proteins, thereby influencing their stability, subcellular localization, and protein-protein interactions [ 59 , 60 ]. Among these isoforms, SUMO2/3 are the primary mediators in the regulation of neuroinflammatory processes. SUMO2/3 molecules are capable of forming poly-SUMO chains through conjugation to lysine residues on adjacent SUMO molecules [ 61 ]. These SUMO2/3 chains function as scaffolding structures within signaling complexes, recruiting regulatory proteins via SUMO-interacting motifs (SIMs) and modulating the assembly and activity of inflammatory signaling platforms in microglia [ 62 ]. Notably, SUMOylation demonstrates a dual role in the polarization of microglia. SUMO2/3 chains play a crucial role in stabilizing anti-inflammatory factors such as nuclear receptor subfamily 4 group A member 1 (NR4A1), thereby suppressing pro-inflammatory signaling and facilitating the resolution of inflammation [ 63 ]. Conversely, deSUMOylation processes, mediated by sentrin/SUMO-specific proteases (SENPs), can negate this protective effect.

The SENP family of enzymes precisely processes SUMO precursors and removes SUMO moieties from substrates, thereby altering the inflammatory status of microglia [ 64 ]. SENP6, known for its potent hydrolytic activity towards SUMO2/3 chains, disassembles poly-SUMO conjugates and releases substrates, thus terminating SUMO-dependent anti-inflammatory signaling. For example, the removal of SUMO2/3 chains from ANXA1 by SENP6 nullifies its inhibitory effect on IKKα, leading to the reactivation of the NF-κB pathway and exacerbation of M1-type pro-inflammatory microglial responses [ 65 ] (Fig. 1 ). Conversely, the pharmacological inhibition of SENP6 prolongs the stability of SUMO2/3 chains on ANXA1, thereby sustaining its anti-inflammatory function [ 65 ]. In an intermittent hypoxia model, SENP1-mediated deSUMOylation of NEMO was associated with the suppression of microglial inflammatory responses. The findings indicate that the effects of NEMO SUMOylation are context-dependent and should not be universally categorized as either pro-inflammatory or anti-inflammatory. This underscores the role of SUMOylation as a pivotal regulatory mechanism influencing microglial inflammatory phenotypes and highlights its potential as a therapeutic target in neuroinflammation [ 66 ]

Recent research demonstrates that enzymes involved in the SUMO pathway, including the E1 activating enzyme, the E2 conjugase Ubc9, various E3 ligases, and SENPs, exhibit dynamic and stage-dependent variations in expression and activity during neuroinflammatory processes [ 64 ]. In the context of acute brain injury or ischemia, an overall increase in SUMOylation is often perceived as a cytoprotective response. Conversely, in chronic neurodegenerative conditions, disturbances in SUMO dynamics can destabilize transcriptional programs and exacerbate inflammation [ 67 ]. Specifically, in microglia, enhancing the SUMOylation of the NFκB p65 subunit or restoring the equilibrium through SENP-mediated deSUMOylation reduces the expression of pro-inflammatory mediators such as TNF-α, IL-1β, and iNOS, inhibits M1 polarization, and mitigates toxicity to adjacent neurons [ 66 , 68 , 69 ]. These observations suggest that targeting SUMOylation or its regulatory enzymes may represent a viable strategy to mitigate pathological microglial activation.

Astrocytes

Astrocytes, which are highly heterogeneous glial cells, play critical roles in synaptic support, maintenance of the blood-brain barrier, and regulation of neuroimmune functions. Traditionally, reactive astrocytes have been classified within the A1/A2 framework: A1-like astrocytes are generally associated with inflammatory responses and potential neurotoxic effects, whereas A2-like astrocytes are linked to neuroprotective or tissue-repair functions. However, emerging evidence indicates that this binary classification is insufficient to capture the complexity of astrocyte activation states, as their phenotypes and functional changes are influenced by a multitude of factors [ 70 ].

Acetylation

Acetylation modulates astrocyte reactivity through two principal mechanisms. The first mechanism involves chromatin-level modifications, where the acetylation of histones H3 and H4 accumulates at the promoters of pro-inflammatory genes, including IL-6, TNF-α, and iNOS, thereby enhancing their transcriptional activity [ 71 ]. The second mechanism pertains to the acetylation of non-histone proteins, such as the NF-κB p65 subunit, which results in increased transcriptional activity and prolonged nuclear retention, thus amplifying inflammatory signaling [ 72 ]. Upon exposure to stimuli such as LPS, Aβ, or IFN-γ, transcription factor networks recruit p300/CBP/GCN5 to specific enhancers and promoters, markedly increasing H3K27ac and H4K16ac levels, thereby enhancing chromatin accessibility and intensifying the inflammatory transcriptional response [ 71 , 73 , 74 ] (Fig. 2 ). Inhibition of the p300/CBP-H3K27ac axis results in the downregulation of pro-inflammatory gene expression, such as Nos2, underscoring the causal role of this pathway in augmenting astrocyte inflammation [ 71 ]. Furthermore, the acetylation of p65 at sites such as K310 is catalyzed by p300/GCN5 and is regulated by the deacetylation activity of HDAC3/SIRT1. This modification augments DNA binding, facilitates the assembly of transcriptional complexes, and promotes nuclear retention, all of which are intricately associated with the maintenance of the inflammatory phenotype [ 75 , 76 ].

At the non-chromatin level, the acetylation of α-tubulin at lysine 40, catalyzed by ATAT1 and modulated by Histone deacetylase 6 (HDAC6) deacetylation, impacts microtubule stability and the efficiency of vesicle transport, thereby influencing processes such as astrocyte dendritic extension, endocytosis, secretion, and migration [ 77 , 78 ]. The selective inhibition of HDAC6 enhances microtubule acetylation, thereby altering these cellular behaviors [ 79 ]. Acetylation also interacts with cytokine signaling; for example, the acetylation of STAT3 at lysine 685 by p300 stabilizes its dimerization and regulates its transcriptional activity. This mechanism provides an acetylation-based regulatory pathway for the IL-6-JAK-STAT3 axis in the phenotypic switching of astrocytes [ 80 , 81 ] (Fig. 2 ). Collectively, these acetylation modifications dictate whether astrocytes assume a neurotoxic/pro-inflammatory or neuroprotective/supportive phenotype.

Pharmacological investigations have demonstrated that the broad-spectrum histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), effectively reduces markers of neuroinflammation and exhibits potential neuroprotective effects across various in vitro and in vivo models [ 82 , 83 ]. In models of ischemia-reperfusion, blood-brain barrier disruption, and metabolic disorders, SAHA has been shown to mitigate inflammation and vascular dysfunction. Additionally, in certain contexts, it inhibits the release of pro-inflammatory cytokines and oxidative stress [ 84 , 85 ]. However, the outcomes are significantly influenced by the specific model and treatment window employed. Recent reviews and experimental data indicate that HDAC inhibitors may exhibit dose-dependent biphasic effects: low doses can increase levels of TNF-α, IL-1β, and other cytokines in certain systems, whereas higher doses or appropriate treatment durations suppress inflammation or induce cytotoxicity [ 86 ]. This highlights the necessity of carefully defining effective and safe dosing and timing parameters in astrocyte research and clinical applications.

Distinct HDAC isoforms, such as HDAC1/3 and HDAC6, exhibit unique physiological outcomes upon inhibition, underscoring the importance of selective inhibitors in both research and clinical contexts [ 87 ]. Nuclear HDAC1/3 is known to associate with co-repressors like NCoR/SMRT, facilitating chromatin deacetylation and the transcriptional repression of genes involved in metabolism and inflammation [ 88 , 89 ]. Conversely, cytoplasmic HDAC6 primarily modulates α-tubulin acetylation and protein homeostasis, playing a critical role in stress granule response and the autophagy-lysosome pathway [ 77 , 90 ]. Consequently, selective inhibition of HDAC6 is particularly effective in targeting the HDAC6-α-tubulin pathway within the cytoplasm. Furthermore, the overexpression of HDAC7 in astrocytes has been shown to activate NF-κB by interacting with the IKK complex, thereby amplifying pro-inflammatory gene expression [ 91 ]. This evidence underscores the necessity for precise inhibition strategies that are tailored to isoform-specific pathways and cellular compartments.

Methylation

Histone methylation, particularly the trimethylation of histone H3 at lysine 27 (H3K27me3), constitutes a fundamental mechanism in the regulation of astrocytic phenotypes and their transcriptional programs [ 92 ]. The catalysis of H3K27me3 is predominantly facilitated by the enzymatic subunit Enhancer of zeste homolog 2 (EZH2), a component of the polycomb repressive complex 2 (PRC2) [ 93 ]. Upon deposition at promoter or enhancer regions, H3K27me3 sustains a repressive chromatin configuration, thereby restricting the transcriptional activity of genes associated with development and inflammation [ 94 ]. The accumulation of H3K27me3, mediated by PRC2, is intricately linked to various phenotypes, including those involving developmental processes and brain-region-specific transcriptional networks [ 95 ]. Empirical evidence from studies utilizing animal models and cell lines indicates that modulation of EZH2 levels or inhibition of PRC2 activity can alter the reactivity spectrum and inflammatory responses of astrocytes [ 96 ], underscoring the significance of the EZH2–H3K27me3 axis as a critical regulatory hub in the formation of reactive astrocytes.

At the molecular level, astrocytes detect damage or pathogen-associated signals via receptors such as Toll-like receptor 4 (TLR4), which subsequently activate transcriptional programs, including NF-κB, and modulate the expression and activity of epigenetic enzymes [ 97 ]. In models of neuroinflammation, the activation of Toll-like receptor 4 (TLR4) is intricately associated with the persistent transcriptional activation of NF-κB and the pro-inflammatory phenotype exhibited by astrocytes [ 98 , 99 ], Concurrently, this process is accompanied by the remodeling of markers associated with EZH2 and PRC2 [ 100 , 101 ]. The opposing demethylation process is facilitated by lysine demethylase 6A (KDM6A, also known as UTX) and KDM6B (also known as JMJD3), which are capable of removing trimethylation at lysine 27 on histone H3 (H3K27me3), thereby alleviating repression at relevant gene loci and promoting the expression of genes associated with inflammation or cellular plasticity [ 102 ] (Fig. 2 ).

Beyond their direct effects on pro-inflammatory effectors, the EZH2/H3K27me3 axis may also modulate inflammatory signaling indirectly by adjusting negative feedback regulators. In astrocytes, suppressor of cytokine signaling 3 (SOCS3) acts as an intrinsic inhibitor of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway; both genetic and pharmacological upregulation of SOCS3 result in attenuated STAT3 activation and a reduction in reactive and inflammatory outputs [ 103 ]. In various models of Alzheimer’s disease, Huntington’s disease, and spinal cord injury, inhibition of JAK/STAT3 signaling or enforced expression of SOCS3 leads to decreased levels of glial fibrillary acidic protein (GFAP) and pro-inflammatory transcripts, supporting the role of SOCS3 as a suppressor in astrocyte-mediated neuroinflammation [ 103 – 105 ]. In myeloid lineages, including central nervous system microglia, the EZH2-mediated deposition of H3K27me3 at the Socs3 promoter represses transcription and enhances inflammatory signaling, thereby providing mechanistic evidence for the upstream epigenetic regulation of the SOCS3/STAT3 pathway [ 106 , 107 ]. Alongside emerging evidence that EZH2 influences astrocyte morphogenesis and function, these findings suggest that this regulatory framework is biologically plausible in astrocytes and merits direct experimental investigation.

The mutually exclusive relationship between acetylation and methylation at the same locus offers critical insights into the epigenetic reprogramming of astrocytes [ 108 ]. While H3K27ac is generally indicative of active enhancers [ 109 ], H3K27me3 is associated with polycomb-mediated repression [ 94 ]. The dynamic interaction between these histone marks, along with changes in chromatin accessibility during disease or injury, collectively determines the reshaping of the transcriptome. Integrating ChIP-seq for H3K27ac/H3K27me3, ATAC-seq, and transcriptomic analyses provides a more precise mapping of the regulatory trajectories and potential therapeutic targets of reactive astrocytes at various stages [ 110 ].

Phosphorylation

Phosphorylation represents a prevalent and reversible post-translational modification that modulates astrocyte reactivity through the dynamic interplay between kinases and phosphatases, thereby influencing the equilibrium between tissue damage and repair in the context of neurodegenerative diseases and acute injuries [ 111 ]. Accumulating evidence suggests that phosphorylation-dependent signaling networks orchestrate the expression of complement components, pro-inflammatory mediators, neurotrophic factors, and remyelination-associated pathways. This regulation positions astrocytes along a context-dependent continuum of reactive states, rather than confining them to a fixed binary axis [ 112 ].

In scenarios characterized by A1-like reactive features, such as exposure to microglia-derived IL-1α, TNF-α, and component 1q (C1q), astrocytes predominantly adopt a pro-inflammatory transcriptional profile [ 113 ]. The activation of the IKK complex results in the phosphorylation and subsequent degradation of IκB, facilitating the nuclear translocation of NF-κB p65 and the upregulation of A1-associated genes, including C3, thus promoting a neurotoxic expression profile [ 114 , 115 ] (Fig. 2 ). In parallel, sustained phosphorylation within the MAPK cascade, particularly involving p38 and c-Jun N-terminal kinase (JNK), along with the accumulation of reactive oxygen species, intensifies the release of chemokines and cytotoxic effectors, thereby exacerbating secondary damage to neurons and oligodendrocytes [ 116 , 117 ]. These phosphorylation events, centered around IKK and MAPK, are intricately linked to the progression of neurodegenerative pathology [ 118 , 119 ].

Conversely, under conditions characterized by A2-like or other reparative astrocyte responses, an anti-inflammatory cytokine milieu enriched with IL-6 and interleukin-10 (IL-10) activates the JAK-STAT3 pathway [ 120 ]. Phosphorylation of STAT3 at Tyr705 facilitates its dimerization and nuclear translocation, initiating the transcription of neurotrophic and anti-inflammatory genes such as brain-derived neurotrophic factor (BDNF), GDNF, and IL-10, thereby establishing a reparative transcriptional program [ 121 , 122 ] (Fig. 2 ). The transcriptional activation dependent on STAT3 is further supported by sequential phosphorylation along the AKT-mTOR axis, which enhances cellular survival and metabolic competence, thereby promoting neurorepair [ 123 ]. Simultaneously, the AKT-mTOR signaling pathway plays a crucial role in maintaining synaptic homeostasis, facilitating the differentiation of oligodendrocyte precursor cells, and enhancing remyelination and tissue reconstruction [ 124 ]. Collectively, these pathways are integral to astrocyte states that contribute to tissue repair and functional recovery.

Phosphorylation functions as both a binary switch and a signal amplifier during the polarization of astrocytes. Specifically, phosphorylation within the IKK-NF-κB and MAPK pathways is predominantly associated with inflammatory and potentially neurotoxic astrocyte programs, whereas signaling dependent on STAT3 and AKT is more frequently linked to neuroprotective and reparative responses. From a translational standpoint, inhibitors targeting the MAPK or NF-κB pathways have the potential to mitigate A1-like reactivity in experimental models; however, due to the widespread expression of these targets across various cell types, their selectivity and safety profiles require thorough evaluation [ 124 , 125 ]. In contrast, within microglia, phosphorylation plays a more direct role in orchestrating canonical immune responses. This is evidenced by the frequent association of p38 MAPK and NF-κB activity with M1-like inflammatory programs, while alternative signaling pathways contribute to anti-inflammatory or repair-associated responses [ 126 ]. In A1 astrocytes, phosphorylation predominantly influences neuronal fate through the NF-κB/MAPK-dependent induction and release of neurotoxic mediators [ 127 ].

Ubiquitination

In astrocytes, ubiquitination utilizes chain-type specific signaling codes to regulate the magnitude and duration of pro-inflammatory versus reparative pathways [ 128 ]. A1 reactivity is closely linked with K63-linked signaling polyubiquitin. Upon stimulation of the interleukin-1 receptor and Toll-like receptors, the E3 ligase TRAF6 collaborates with Ubc13/Uev1A to assemble K63 chains, which are recognized by TAB2 to facilitate the activation of TAK1 and IKK. This process drives NF-κB-dependent inflammatory transcription and the upregulation of A1 markers, such as C3 [ 26 , 129 , 130 ]. Conversely, deubiquitinases disassemble signaling chains or reset key nodes to modulate this pathway. CYLD enzymatically removes K63 and linear M1 ubiquitin chains from proteins such as TRAF6 and NEMO, resulting in decreased NF-κB activity and a consequent reduction in inflammatory responses [ 38 , 131 ] (Fig. 2 ). Further research suggests that USP15 can modulate NF-κB pathway activity in a context-dependent manner [ 132 ], indicating potential condition-specific effects on A1 astrocyte reactivity.

A2-like astrocytes predominantly utilize JAK-STAT3 signaling to maintain neurotrophic and reparative gene expression, with ubiquitination exerting bidirectional control through selective protein degradation and stabilization [ 133 ]. SOCS1, via its SOCS box, forms an E3 ligase complex with Elongin B/C and Cullin 5, facilitating K48-linked ubiquitination and subsequent proteasomal degradation of JAK kinases and, in certain contexts, STAT proteins [ 134 ]. This process attenuates STAT3-driven transcription and diminishes the expression of protective factors, including VEGF [ 23 , 135 , 136 ]. Conversely, the deubiquitinase USP9X has been shown to remove ubiquitin chains from components of the JAK2–STAT3 signaling axis, thereby stabilizing these proteins and sustaining pathway activation. The majority of the existing evidence supporting the role of USP9X in stabilizing JAK2–STAT3 signaling originates from studies conducted in non-CNS models, such as leukemia cells [ 137 , 138 ]. Consequently, it remains to be empirically determined whether USP9X exerts a similar regulatory influence on JAK2–STAT3 signaling within astrocytes under conditions of neuroinflammation (Fig. 2 ).

In terms of chain-type to pathway correlation, K63-linked ubiquitin chains primarily function as scaffolds that enhance the A1 proinflammatory cascade, while K48-linked chains are more frequently involved in the selective degradation processes associated with A2-related JAK-STAT signaling. Additionally, the linear M1-linked chain, which serves as an auxiliary signal within the NF-κB pathway, is meticulously regulated by CYLD and other related deubiquitinases [ 139 ]. This delineation of chain architecture in relation to pathway dynamics offers a comprehensive framework for understanding the equilibrium between inflammatory and reparative processes in astrocytes. It also underpins therapeutic approaches that target the TRAF6–TAK1-IKK module, the SOCS1–CUL5 complex, or USP-family deubiquitinases to achieve programmable modulation of A1-like and A2-like states.

Oligodendrocyte

Ubiquitination

Ubiquitination serves as a pivotal post-translational modification within the oligodendrocyte lineage. Different ubiquitin chain linkages impart distinct destinies to substrate proteins: K48-linked polyubiquitin chains primarily direct proteins towards degradation via the 26S proteasome, whereas K63-linked and linear chains are predominantly involved in non-proteolytic functions, such as the assembly of signaling scaffolds, complex formation, and receptor trafficking [ 140 ]. In oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes, this chain-type coding system is essential not only for maintaining global protein homeostasis but also for adapting to metabolic stress, making lineage fate decisions, and dynamically regulating myelin protein abundance [ 141 ].

Under conditions of hypoxia or metabolic stress, hypoxia-inducible factor 1 alpha (HIF-1α) emerges as a critical determinant of OPC behavior. The persistent stabilization of HIF-1α in OPCs triggers the expression of non-canonical target genes, suppresses Sox10-driven myelin transcriptional networks, and results in differentiation arrest and remyelination failure [ 142 , 143 ]. In models of white matter ischemia and chronic hypoperfusion, the activation of HIF-1α in conjunction with endothelial PAS domain protein 1 (Epas1) within OPCs enhances the expression of VEGFA, leading to disruption of the BBB and exacerbation of white matter injury [ 144 ]. Consequently, the homeostasis of HIF-1α protein serves as a pivotal connection between hypoxia sensing, metabolic reprogramming, and the regenerative potential of the oligodendrocyte lineage.

Mechanistically, the degradation of HIF-1α is predominantly facilitated by Lysine 48-linked ubiquitin chain-linked (K48-linked) polyubiquitin chains. Under normoxic conditions, prolyl hydroxylase domain (PHD) enzymes hydroxylate specific proline residues on HIF-1α, enabling recognition by the von Hippel-Lindau (VHL) E3 ligase complex, which subsequently assembles K48-linked chains that target HIF-1α for proteasomal degradation [ 145 ] (Fig. 3 ). Metabolism-associated modifications, such as lactylation, can attenuate the interaction between HIF-1α and the VHL complex, diminish K48 chain attachment, and prolong the half-life of HIF-1α, thereby providing a molecular basis for its aberrant stabilization in ischemic or highly glycolytic environments [ 146 ]. Within this regulatory framework, the E3 ligase lethal (3) malignant brain tumor-like protein 3 (L3MBTL3) functions as an inducible negative regulator by enhancing K48-linked ubiquitination of HIF-1α under hypoxic conditions, thereby promoting its degradation [ 147 ]. These findings suggest that the VHL complex, along with auxiliary factors such as L3MBTL3, rather than Parkin, are the primary determinants of HIF-1α stability in this context [ 148 ].

Conversely, several DUBs stabilize HIF-1α by counteracting K48-linked ubiquitin chains. Under hypoxic conditions, the ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) inhibits K48-linked ubiquitination of HIF-1α, leading to its increased abundance and enhanced downstream transcriptional responses [ 149 ]. VHL-associated DUBs, such as ubiquitin-specific peptidase 20 (USP20), can similarly remove degradative ubiquitin chains, thereby reducing the proteasomal degradation of HIF-1α [ 150 ]. Sustained upregulation of these DUBs in the oligodendrocyte lineage is anticipated to lower the degradation threshold of HIF-1α, maintain OPCs in a high-HIF state, and potentially impair their differentiation and remyelination capabilities [ 151 ].

In addition to its direct regulation of HIF-1α, the ubiquitin-proteasome system (UPS) plays a crucial role in modulating oligodendrocyte function by ensuring the quality control of myelin proteins and managing endoplasmic reticulum (ER) stress. Within oligodendrocytes, the unfolded protein response (UPR) and ER-associated degradation (ERAD) pathways are instrumental in identifying and eliminating misfolded myelin proteins, thereby preserving the integrity of the myelin membrane proteome [ 141 , 152 ]. Disruption of these pathways results in the accumulation of proteolipid protein (PLP) and myelin basic protein (MBP), leading to oligodendrocyte apoptosis and subsequent demyelination [ 153 ]. Proteomic and structural analyses further reveal that MBP is particularly vulnerable to proteasomal degradation under inflammatory conditions, with its degradation efficiency being contingent upon its ubiquitination status and the specific phenotype of the proteasome. This process may expose neoepitopes, thereby contributing to autoimmune-mediated myelin damage [ 154 ]. In both inherited and acquired white matter disorders, the concurrent dysfunction of the UPS and autophagy is increasingly recognized as a prevalent factor driving oligodendrocyte failure and progressive myelin degeneration [ 155 ].

Phosphorylation

Phosphorylation serves as a crucial signaling nexus in the development and myelination of oligodendrocytes (OLs). Developmental signals are transduced through the PI3K-Akt-mTOR pathway into growth- and metabolism-promoting signals that directly facilitate myelin membrane expansion and enhance sheath thickness [ 124 , 156 ]. Upon phosphorylation, Akt activates mTORC1, which subsequently phosphorylates S6K1 and 4E-BP1, alleviating translational repression and augmenting the synthesis of myelin-specific proteins, particularly MBP, thereby improving the efficiency of myelin assembly [ 157 , 158 ] (Fig. 3 ). Both in vitro and in vivo studies have demonstrated that activation of Akt or mTORC1 results in thicker myelin sheaths and improved axonal ensheathment, whereas inhibition of this pathway delays myelination or restricts remyelination [ 124 , 159 ]. It is imperative to maintain mTOR signaling within a precisely regulated dynamic range, as excessive or prolonged activation can induce aberrant growth signals, metabolic imbalance, and translational overload, ultimately compromising myelin structure and function [ 160 ]. Consequently, the activity of mTOR demonstrates distinct temporal and dosage-dependent effects during developmental myelination and adult remyelination processes [ 158 ].

At the molecular and metabolic levels, mTORC1 facilitates translation by phosphorylating S6K1 and 4E-BP1, while also enhancing lipid and cholesterol biosynthesis to satisfy the high lipid requirements of myelin membrane [ 161 , 162 ] (Fig. 3 ). Furthermore, mTORC1 phosphorylates TFEB, thereby inhibiting its translocation to the nucleus and suppressing the transcription of genes related to autophagy and lysosome function [ 163 , 164 ]. This interaction establishes a functional antagonism between mTORC1 and the autophagy-lysosome system, suggesting that this pathway not only regulates protein synthesis but also maintains cellular homeostasis by modulating organelle turnover [ 164 ]. In OLs, moderate autophagy is crucial for the removal of damaged organelles and the maintenance of metabolic balance, particularly during myelin repair and regeneration [ 165 ].

Recent cell type-specific genetic studies have demonstrated that OPCs and mature OLs exhibit distinct dependencies on and response patterns to mTOR signaling [ 166 , 167 ]. During development, increased mTOR activity facilitates the differentiation of OPCs and the formation of myelin [ 168 ], In contrast, in regenerative scenarios post-injury, it is crucial to finely modulate mTOR activity to support remyelination without causing metabolic overload [ 159 ]. Consequently, future therapeutic approaches should consider the specificity of cell types and the stage of the disease to selectively and temporally regulate mTOR signaling, with the goal of safely and effectively promoting remyelination in neurodegenerative and demyelinating diseases.

Acetylation

Acetylation plays a critical role in regulating the acetylation status of both histone and non-histone substrates, thereby altering chromatin accessibility and transcription factor activity, which in turn affects OL proliferation, differentiation, and myelin formation [ 169 ]. The NAD + -dependent deacetylase SIRT1 acts as a pivotal upstream regulator in this network, exerting stage-specific effects on OPCs and mature OLs under various developmental and pathological conditions [ 170 ]. The activity of SIRT1 has been shown to support the survival and proliferation of OPCs; however, under certain conditions, it may inhibit their differentiation, indicating a complex regulatory role that is intricately associated with lineage state, metabolic signals, and the surrounding microenvironment [ 171 ]. In certain demyelination models, inhibition of SIRT1 leads to an increase in OPC abundance and promotes remyelination [ 172 , 173 ], whereas during early developmental stages, SIRT1 activity seems to be crucial for maintaining OPC homeostasis and proliferation [ 171 ]. These observations imply that therapeutic strategies targeting SIRT1 should be carefully tailored to the specific disease stage and cellular context.

At the chromatin level, histone deacetylases HDAC1, HDAC2, and HDAC3 modulate oligodendrocyte gene expression by deacetylating histones H3 and H4, thereby regulating the expression of genes critical for myelin formation, such as MBP and PLP [ 80 , 174 ] (Fig. 3 ). While moderate deacetylation supports the establishment of lineage-specific transcriptional programs, excessive deacetylation is linked to nuclear stress and disturbances in protein folding and degradation pathways, ultimately compromising remyelination efficiency and myelin stability [ 175 , 176 ]. At the level of cytoskeletal and membrane transport, HDAC6 deacetylates α-tubulin, thereby modulating microtubule stability, process extension, and vesicle transport dynamics [ 177 , 178 ] (Fig. 3 ). This regulatory mechanism dictates the polarized trafficking of myelin membrane precursors and the localization of myelin-specific proteins at distal processes, which are essential for the expansion of the myelin membrane and the geometry of axonal ensheathment. Consequently, the acetylation state of microtubules serves as a critical determinant of the rate of myelination and its structural integrity [ 179 ].

In the context of non-histone signal integration, SIRT1 has been demonstrated to directly deacetylate Cdk2 and the retinoblastoma protein Rb in OPCs, while also modulating the acetylation status of the transcription factor FoxO3a. Through these coordinated actions, SIRT1 remodels the Cdk2/Rb/E2F1 and FoxO3a pathways, thereby linking hypoxia-related metabolic signals to the progression or arrest of the OPC cell cycle [ 171 ]. Concurrently, under inflammatory conditions, sublytic C5b-9 activates a c-Jun-PI3K-PKC signaling cascade that upregulates SIRT1. This process is associated with increased levels of H3K9me3 and cyclin D1, along with a transient downregulation of MBP and PLP [ 180 ]. These events collectively refine the temporal coordination between OPC proliferation and myelin protein expression during the process of remyelination following white matter injury. Unlike microglia, where acetylation primarily regulates inflammatory transcriptional activity, in OLs, acetylation predominantly influences chromatin programming, microtubule dynamics, and membrane biogenesis [ 181 , 182 ]. Therefore, future therapeutic strategies should focus on interventions that are specific to cell type and timing, utilizing selective modulation of SIRT1 and specific HDACs, such as HDAC6, to enhance myelin repair while minimizing broad immune suppression and metabolic disturbances [ 183 ]. The use of local or nanocarrier-based drug delivery systems may further improve targeting precision and safety [ 184 ].

S-nitrosylation

SNO is a redox-dependent PTM wherein nitric oxide (NO) and related reactive nitrogen species covalently modify cysteine residues. SNO dynamically regulates enzymatic activity, protein-protein interactions, and mitochondrial function, and its activity is significantly increased under conditions of inflammatory or oxidative stress [ 185 ]. While the pathological roles of SNO have been extensively studied in neurons and astrocytes, particularly concerning protein misfolding, mitochondrial dysfunction, and synaptic loss in Alzheimer’s disease (AD) [ 186 ], there is a paucity of direct evidence identifying specific SNO-modified substrates and their functional consequences in OLs. Consequently, several mechanisms discussed herein are primarily extrapolated from findings in other neural or non-neural systems and necessitate direct validation in OL lineage cells [ 187 , 188 ].

Given the substantial metabolic demands of OLs for myelin synthesis and maintenance, mitochondrial dysfunction emerges as a potential mechanism through which SNO may impact OL survival and function. Research conducted in neuronal models and isolated synaptic preparations has demonstrated that SNO modification of mitochondrial respiratory chain components, such as complex I and II subunits, can impair electron transport and diminish ATP production [ 189 – 191 ]. Nonetheless, it remains uncertain whether similar SNO modifications occur in OLs and contribute to myelin impairment. Based on the metabolic reliance of OLs, persistent S-nitrosylation (SNO)-induced mitochondrial dysfunction may potentially compromise the maintenance of myelin or heighten the susceptibility of OLs under inflammatory conditions (refer to Fig. 3 ).

Furthermore, the SNO-mediated regulation of molecular chaperones, such as heat shock protein 70 (Hsp70), and components of the proteasome, including the 26S proteasome complex, has predominantly been documented in neuronal systems, synaptic fractions, and other cellular models, rather than directly in OLs [ 192 , 193 ]. These observations imply that disruptions in protein folding and degradation could constitute a potential mechanism contributing to OL stress. Nevertheless, whether SNO-induced modifications of myelin proteins, such as PLP and MBP, occur within OLs and facilitate protein aggregation or immune activation remains to be empirically validated. Additionally, the regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling by SNO has been primarily demonstrated in immune cells, endothelial cells, vascular smooth muscle cells, and neuronal models [ 194 , 195 ] (Fig. 3 ). In the context of neuroinflammation, activated microglia can produce excessive nitric oxide (NO), potentially increasing the exposure of adjacent OLs to nitrosative stress, thereby contributing to OL apoptosis or dysfunction [ 196 ]. The specific SNO targets that connect nitric oxide (NO) elevation to oligodendrocyte (OL) injury have yet to be precisely identified. Although elevated SNO levels have been correlated with demyelination and neurological deficits in various disease models [ 197 ], it remains unclear whether these changes are due to direct SNO modifications within OLs or are secondary effects arising from adjacent inflammatory cells, necessitating further investigation.

Despite progress in this area, the exact sites of SNO modification in OLs are still largely unknown. Future research should integrate high-resolution SNO proteomics with cell lineage-specific tracing methodologies to elucidate modification patterns and establish causal relationships with OL dysfunction [ 198 ]. Recent studies have highlighted the importance of applying SNO-proteomic profiling to both OPCs and mature OLs to identify critical SNO targets and elucidate their roles in the processes of myelination and remyelination [ 198 , 199 ].

PTMs regulate peripheral immune cell infiltration and changes in BBB permeability

T cells

In various chronic neuroinflammatory disorders, peripheral CD4-positive T cells infiltrate the central nervous system by crossing the compromised BBB, a critical event in perpetuating the inflammatory cascade. Within this context, T helper type 1 (Th1) and T helper type 17 (Th17) cells emerge as the predominant pathogenic subsets [ 200 ]. Th1 cells secrete interferon gamma, which activates the JAK1/JAK2–STAT1 signaling pathway, leading to the upregulation of inducible nitric oxide synthase and interleukin-6 (IL-6). This process enhances proinflammatory microglial polarization and reactive astrogliosis [ 201 , 202 ] (Fig. 4 ). Conversely, Th17 cells produce interleukin-17 (IL-17) and related cytokines, which increase the expression of adhesion molecules on brain microvascular endothelial cells and compromise tight junction integrity. This results in heightened BBB permeability, exacerbating demyelination and neuronal damage [ 203 ]. In opposition to these effects, regulatory T cells mitigate the expansion of effector T cells and the overactivation of glial cells through the secretion of IL-10 and transforming growth factor beta (TGF-β), thereby preserving immune tolerance and facilitating tissue repair, ultimately exerting a neuroprotective effect [ 204 ].

Post-translational modifications of proteins introduce an additional regulatory layer that fine-tunes T-cell responses by establishing signaling thresholds. The Cbl family of E3 ubiquitin ligases plays a crucial role in this process by ubiquitinating key proximal signaling components of the T-cell receptor, such as ZAP70 and LAT. This ubiquitination targets these components for degradation, thereby modulating the intensity and duration of T-cell receptor signaling, which serves to constrain the proliferation of high-affinity autoreactive clones [ 205 ]. A reduction in Cbl-mediated regulation results in enhanced Th1 and Th17 responses, increased infiltration into the central nervous system, and exacerbated tissue damage [ 206 ]. Similarly, lysine acetylation and deacetylation are critical in determining the balance of T-helper cell subsets. SIRT1, a deacetylase, targets non-histone substrates including NF-κB, STAT1, and STAT3, thereby suppressing pro-inflammatory transcriptional programs while facilitating the generation of regulatory T cells and restricting pathogenic Th17 differentiation [ 207 , 208 ]. In microglia and astrocytes, SIRT1-dependent deacetylation of STAT1 and STAT3 leads to the downregulation of inducible nitric oxide synthase and IL-6, while relatively enhancing the expression of IL-10, IL-4, and IL-13 [ 52 , 209 ]. This establishes an anti-inflammatory feedback loop between the STAT1 and STAT3 branches and the STAT6 pathway, as illustrated in Fig. 4 .

Glycosylation further modulates T-cell adhesion and migration across the BBB by remodeling the endothelial glycocalyx [ 210 ]. N-linked and O-linked glycans on adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on brain microvascular endothelium, dictate their affinity for integrins, directly influencing T-cell rolling, firm adhesion, and transmigration efficiency [ 211 , 212 ]. The N-glycosylation status of the microglial receptor TREM2 is critical for its surface expression and signal transduction; impaired glycosylation compromises amyloid clearance and biases microglia toward a pro-inflammatory phenotype, thereby reshaping the innate immune environment encountered by infiltrating T cells [ 213 ]. Phosphorylation plays a crucial role in the regulation of T-cell migration and BBB permeability. In T cells, initial phosphorylation events mediated by Src family kinases and ZAP70 play a crucial role in enhancing T-cell receptor signaling [ 214 ]. Concurrently, the phosphorylation status of PI3K-Akt and small GTPases influences focal adhesion dynamics and actin cytoskeleton remodeling, directing Th1 and Th17 cells toward inflamed brain regions [ 215 , 216 ]. Within the brain microvascular endothelium, signaling pathways downstream of VEGF and its receptor, along with various cytokine receptors, activate the JAK-STAT pathways. This activation alters the phosphorylation of tight-junction and adherens-junction proteins, temporarily increasing barrier permeability and creating a window of opportunity for effector T-cell entry into the parenchyma [ 217 ]. In alignment with the model depicted in Fig. 4 , interferon gamma, IL-6, and IL-4 produced by Th1 and Th2 cells preferentially activate STAT1, STAT3, or STAT6, respectively. This establishes a dynamic balance between pro-inflammatory and anti-inflammatory gene programs, underscoring the JAK-STAT and VEGF signaling pathways as critical therapeutic targets to mitigate pathogenic T-cell infiltration and reprogram glial responses [ 19 , 218 ].

B cells

In CNS autoimmune disorders, the role of B cells has evolved from being perceived solely as antibody producers to being acknowledged as crucial effector cells that both drive and modulate neuroinflammation [ 219 ]. In conditions such as multiple sclerosis, clonally expanded B cells accumulate within the cerebrospinal fluid and meningeal compartments, where they persistently produce anti-myelin antibodies and form localized immune infiltrates [ 220 ]. Concurrently, these B cells present myelin antigens and secrete cytokines, such as IL-6, thereby altering glial inflammatory states [ 221 ].

PTMs represent a vital signaling layer that links antigen recognition to effector differentiation. Following B-cell receptor (BCR) engagement, Src-family kinases and Syk induce multisite phosphorylation of the receptor complex, facilitating the assembly of downstream signalosomes and activating the NF-κB, PI3K-Akt, and MAPK pathways, which are critical for determining proliferation, class-switch recombination, and affinity maturation [ 222 , 223 ]. Dysregulated signaling thresholds predispose to the emergence of autoreactive clones targeting myelin antigens [ 224 ]. Ubiquitination modulates signaling amplitude by influencing the stability of critical signaling intermediates. Cbl-family E3 ligases facilitate the polyubiquitination and subsequent degradation of proximal molecules, thereby terminating B-cell receptor (BCR) signaling [ 225 ]. In contrast, TRAF-dependent ubiquitin complexes function within the BAFF-BAFFR and CD40 pathways to activate non-canonical NF-κB signaling, thereby supporting the survival of pathogenic B-cell subsets [ 226 ]. Additionally, glycosylation plays a crucial role in modulating antibody effector functions; modifications in IgG Fc N-glycans can alter the equilibrium between antibody-dependent cytotoxicity and anti-inflammatory activity. Aberrant glycoforms are associated with disease activity and neuroaxonal injury [ 227 ].

Cytokines secreted by B cells exert their effects on CNS-resident immune cells, such as microglia and astrocytes, through the JAK-STAT signaling pathway and acetylation-deacetylation mechanisms. Specifically, IL-6 promotes STAT3 phosphorylation and the expression of pro-inflammatory genes in microglia and astrocytes, whereas interleukins IL-10, IL-4, and IL-13 preferentially activate STAT3 and STAT6, leading to the production of anti-inflammatory mediators and neurotrophic factors [ 228 – 230 ]. The deacetylase SIRT1 mitigates these responses through the deacetylation of STAT3 and NF-κB p65, thereby suppressing their transcriptional activity and providing negative feedback to B-cell-derived inflammatory signals [ 231 ]. Therapeutic outcomes vary among B-cell-targeted strategies. While anti-CD20-mediated B-cell depletion has shown clinical efficacy in multiple sclerosis (MS), BAFF blockade has been effective in reducing meningeal inflammation and protecting against synaptic and neuronal loss in an experimental autoimmune encephalomyelitis (EAE) model [ 232 , 233 ]. However, these preclinical findings should not be directly extrapolated to MS patients. In the phase 2 ATAMS trial, atacicept was associated with increased clinical disease activity, resulting in the early termination of the study [ 234 ]. Furthermore, the pro-inflammatory IgG1 Fc glycosylation pattern observed in the cerebrospinal fluid of MS patients may contribute to pathogenic antibody effector functions [ 235 ].

Macrophages

Among peripheral myeloid cells, perivascular macrophages located within the perivascular space function as sentinels, facilitating communication between the systemic circulation and the brain parenchyma, and are crucial for immune surveillance and the maintenance of BBB homeostasis [ 236 ]. Alongside endothelial cells, pericytes, and astrocytic endfeet, they constitute a vital component of the neurovascular unit. Under normal physiological conditions, perivascular macrophages play a role in clearing metabolic by-products, regulating cerebral blood flow, and preserving barrier integrity [ 237 ]. However, in the context of neurodegenerative and cerebrovascular diseases, phenotypic reprogramming and alterations in their cytokine profiles contribute to BBB disruption and the exacerbation of neuroinflammation [ 238 ].

PTMs serve as a critical regulatory mechanism that influences the inflammatory phenotype of perivascular macrophages and their ability to transmit signals across the barrier. Pathogen-associated and damage-associated molecular patterns activate Toll-like receptors, resulting in the recruitment of TRAF6 and the formation of K63-linked ubiquitin chains, which subsequently engage downstream kinase cascades [ 239 ]. This process initiates the phosphorylation of Inhibitor of nuclear factor kappa-B alpha (IκBα), followed by K48-linked ubiquitination and subsequent degradation, thereby facilitating the translocation of NF-κB into the nucleus to commence the transcription of proinflammatory cytokines and chemokines [ 240 ]. The phosphorylation, SUMOylation, and deacetylation of the NF-κB p65 subunit interact with ubiquitination to precisely regulate its transcriptional activity and nuclear retention time, thereby establishing a modifiable equilibrium between the amplification and resolution of inflammation. In macrophages, NF-κB-dependent priming and subsequent activation of the NLRP3 inflammasome in response to danger signals promote the activation of caspase-1 and the maturation of IL-1β and Interleukin-18 (IL-18). The stability and activity of NLRP3 can be further modulated through ubiquitination and deubiquitination [ 241 , 242 ]. While these mechanisms are well-documented in macrophages, their specific roles in brain perivascular macrophages necessitate further investigation. Nonetheless, the release of inflammasome-associated cytokines from myeloid cells may contribute to the dysfunction of the blood-brain barrier and the recruitment of circulating immune cells (Fig. 4 ).

Based on this framework, perivascular macrophages influence the permeability of the BBB and modulate glial responses through altered cytokine and exosome profiles. Specifically, interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and IL-6 facilitate the degradation of endothelial tight junction proteins and the upregulation of adhesion molecules [ 243 ]. These cytokines activate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways in endothelial cells and pericytes, thereby enhancing leukocyte adhesion and transendothelial migration [ 244 , 245 ]. Furthermore, these cytokines penetrate the compromised BBB and exert effects on microglia and astrocytes, where receptor-mediated JAK-STAT signaling cascades reprogram inflammatory and immune gene expression, establishing a feed-forward loop that links proinflammatory microglial activation, reactive astrogliosis, and neuronal injury [ 246 ] (Fig. 4 ). Additionally, macrophage-derived exosomes containing post-translationally modified proteins and microRNA complexes can activate the NF-κB/matrix metalloproteinase (MMP) axis in brain endothelial cells, promoting MMP-dependent degradation of the basement membrane and tight junctions, and inducing endothelial cell apoptosis [ 247 , 248 ]. In contrast, exosomes containing anti-inflammatory cargo, such as NF-κB inhibitors or regulatory microRNAs, have the potential to mitigate the harmful interactions between macrophages and microglia. This underscores the significance of vesicle-mediated post-translational modification signaling as a promising strategy for the therapeutic modulation of neuroinflammation associated with the blood-brain barrier.

Blood-brain barrier

The BBB serves as the primary defensive interface that maintains the homeostatic microenvironment of the central nervous system [ 249 ]. It is constituted by brain microvascular endothelial cells, pericytes, astrocytic endfeet, and the surrounding basement membrane. Among these components, the highly specialized tight junction complexes between endothelial cells, characterized by proteins such as occludin, claudin-5, and the scaffolding protein ZO-1, are crucial in determining the selective permeability of the barrier, thereby exerting tight control over the passage of ions, nutrients, and immune cells [ 250 ]. Emerging evidence suggests that these tight junction proteins are not merely static structural elements but are subject to continuous regulation through PTMs [ 251 ]. Processes such as phosphorylation, ubiquitination, and glycosylation dynamically influence protein conformation, intracellular trafficking, and degradation, thus fine-tuning the opening threshold and repair capacity of the BBB under inflammatory conditions [ 252 , 253 ].

During systemic inflammation or infection, Toll-like receptors expressed on brain endothelial cells and perivascular myeloid cells can be activated by ligands such as lipopolysaccharide [ 254 ]. This initiates a signaling cascade involving TRAF6, TAK1, and the IKK complex, resulting in the phosphorylation and degradation of IκB, the nuclear translocation of NF-κB, and the induction of IL-6, TNF-α, IL-1β, and various matrix metalloproteinases [ 255 ]. Consequently, the downregulation of occludin, claudin-5, and ZO-1 compromises tight junction integrity and increases barrier permeability, consistent with the NF-κB-centered axis illustrated in the macrophage module of the schematic [ 256 ] (Fig. 4 ). Concurrently, VEGF signaling through VEGFR2 in brain endothelial cells triggers multi-site phosphorylation events that facilitate tight junction protein endocytosis and cytoskeletal remodeling, further exacerbating BBB disruption [ 257 ].

Tight junction proteins themselves are direct targets of PTMs. Under physiological conditions, the phosphorylation of serine and tyrosine residues on occludin enhances junctional stability and barrier function [ 258 ]. In contrast, exposure to inflammatory cytokines or VEGF modifies the phosphorylation pattern of occludin, creating motifs recognized by specific E3 ubiquitin ligases [ 259 ]. Subsequent ubiquitination facilitates the endocytosis of occludin, directing it towards lysosomal or proteasomal degradation [ 259 ]. Experimental investigations have demonstrated that IL-6 can upregulate E3 ligases, such as UBR1, in brain endothelial cells, thereby augmenting the ubiquitination and subsequent degradation of occludin, as well as certain subsets of claudin-5 and ZO-1. This process contributes to the further disassembly of tight junctions [ 260 ]. Furthermore, IL-6 and IL-22 activate the JAK-STAT signaling pathway, leading to the phosphorylation of STAT3, which in turn suppresses the transcriptional expression of tight junction genes [ 255 , 261 ]. Pharmacological inhibition of this signaling axis significantly mitigates the breakdown of the BBB, highlighting the critical role of cytokine-driven PTM networks in barrier regulation.

The deacetylase SIRT1 has been identified as a pivotal negative regulator that integrates PTM signaling with inflammatory responses at the BBB. Enhancing SIRT1 activity in brain endothelial cells results in the upregulation of claudin-5 and occludin, suppression of oxidative stress and inflammatory mediator production, and alleviation of chronic barrier leakage in the context of aging and ischemic brain injury [ 262 ]. Mechanistically, SIRT1 exerts its regulatory function by deacetylating NF-κB p65 and STAT3, which leads to a reduction in their transcriptional activity and provides feedback inhibition to both the NF-κB and JAK-STAT signaling pathways. This is consistent with SIRT1‘s role at the intersection of multiple signaling modules, as depicted in the schematic [ 263 ]. Furthermore, modifications in the glycosylation patterns of the endothelial glycocalyx and adhesion molecules, such as ICAM-1 and VCAM-1, alter their affinity for leukocytes, thereby influencing processes such as adhesion, rolling, and transendothelial migration (Fig. 4 ). Additionally, the glycosylation status of tight junction proteins affects their stability and membrane localization [ 264 , 265 ]. Collectively, these layers of post-translational modification-dependent regulation provide an additional level of precise control over blood-brain barrier permeability in the context of neuroinflammation.

PTMs regulation across cell types, disease stages, and signaling pathways

Based on the comparative evidence across different neuroimmune cell types summarized in Table 1 , the biological function of a PTM cannot be deduced solely from its modification class. Instead, it is influenced by factors such as the enzyme responsible for addition or removal, the identity of the substrate, the architecture of the modified residue or chain, subcellular localization, cellular state, and temporal dynamics. These variables serve as common axes for comparison, enabling the evaluation of PTM mechanisms across various neural cell types, disease triggers, and pathological stages, without attributing a fixed pro- or anti-inflammatory role to a specific modification.

Different cell types and cell‑cell interactions

Microglia, astrocytes, and oligodendrocyte-lineage cells frequently utilize signaling modules such as p38, IKK, JAK-STAT, TRAF6, SIRT1, and mTOR; however, these modules target distinct substrates in different contexts. For instance, in microglia, p38 phosphorylates transcriptional regulators such as ATF2 and ELK1, thereby enhancing the expression of pro-inflammatory cytokines IL-1β, TNF-α, and IL-6 [14, 15] . Additionally, IKK-mediated phosphorylation of IκBα at Ser32/Ser36 facilitates its recognition by the SCF–β-TrCP complex, leading to K48-linked ubiquitination and subsequent degradation. The released p65 subunit undergoes further regulation through Ser536 phosphorylation and Lys310 acetylation, which modulate its nuclear activity and influence inflammatory gene transcription [ 53 ]. These events predominantly influence cytokine release, inflammasome priming, and phagocytic behavior.

In astrocytes, the phosphorylation of IκBα and the nuclear translocation of p65 similarly contribute to the expression of C3 and inflammatory genes. Concurrently, the phosphorylation of STAT3 at Tyr705 facilitates STAT3 dimerization and subsequent nuclear entry during reactive astrogliosis [ 81 , 99 ]. However, a direct astrocytic substrate of p38 that singularly accounts for C3 induction has not been identified. Current evidence suggests that p38/JNK acts upstream of transcription associated with AP-1 and NF-κB, rather than supporting a straightforward p38–C3 substrate relationship. This distinction is crucial: inhibiting the pathway may reduce C3 levels without confirming that C3 production is governed by a direct phosphorylation event by p38. Astrocytes also contain non-transcriptional PTM substrates. The deacetylation of α-tubulin at Lys40, mediated by HDAC6, influences process extension and vesicular transport, whereas the ubiquitination of GLT-1, dependent on PKC, affects its membrane stability and glutamate uptake [ 78 , 266 ].

In cells of the oligodendrocyte lineage, the primary phosphorylation substrates are linked to differentiation and myelin synthesis. Akt activates mTORC1, which subsequently phosphorylates S6K1 and 4E-BP1, thereby enhancing protein translation. Concurrently, the phosphorylation of TFEB limits its nuclear translocation and the expression of lysosomal genes [ 157 , 163 ]. These molecular events are particularly pertinent to the differentiation of OPCs, as mature oligodendrocytes exhibit a greater reliance on proteostasis, cytoskeletal transport, and the maintenance of existing myelin. Histone deacetylases HDAC1 and HDAC2 modulate chromatin programs associated with differentiation, whereas HDAC6-mediated deacetylation of α-tubulin regulates the transport of myelin components [ 174 , 177 ]. Consequently, the same class of PTMs governs cytokine production in microglia, reactive transcription in astrocytes, and the synthesis of proteins or lipids in oligodendrocyte-lineage cells, due to the variation in modified substrates.

The process of ubiquitination further illustrates the necessity of specifying both substrate and chain topology. Specifically, K63- and M1-linked ubiquitin chains on receptor-proximal components such as TRAF6 and NEMO facilitate the assembly of TAK1-IKK signaling complexes. Similarly, CHIP-mediated K63-linked ubiquitination of TAK1 enhances NF-κB activity [ 267 ]. In contrast, K48-linked ubiquitin chains facilitate protein degradation, yet the functional outcomes are substrate-specific: degradation of IκBα results in the release of NF-κB, whereas MARCH2-mediated degradation of NEMO and TRIM31-mediated degradation of NLRP3 serve to attenuate inflammatory signaling pathways [ 43 , 268 ]. Within oligodendrocyte-lineage cells, the VHL-mediated ubiquitination of HIF-1α and the endoplasmic reticulum-associated degradation of misfolded myelin proteins primarily influence OPC differentiation and the integrity of myelin, rather than exerting direct control over cytokine release [ 142 ]. Consequently, it is inappropriate to broadly categorize K48-linked ubiquitination as anti-inflammatory.

PTM-dependent responses also propagate intercellularly. Microglial production of IL-1α, TNF-α, and C1q activates NF-κB and STAT signaling pathways in astrocytes, while astrocyte-derived ATP, cytokines, lactate, and extracellular matrix signals reciprocally modulate microglial kinase activity and metabolic PTMs. The activation of microglial phagocytic pathways by myelin debris, and the subsequent efficiency of its clearance, critically influences whether OPC differentiation is promoted or inhibited. Neurons actively participate in these regulatory feedback loops. The post-translational modifications of neuronal tau, including phosphorylation, acetylation, and ubiquitination, significantly impact its aggregation, degradation, and release processes. Once released extracellularly, tau can activate microglial TLR2–MyD88/NF-κB signaling pathway [ 269 , 270 ]. In contrast, excessive complement-dependent microglial phagocytosis contributes to synaptic loss [ 271 ], while compromised stability of astrocytic GLT-1 exacerbates excitotoxic stress [ 266 ]. The convergence of cellular processes is driven by shared molecular pathways and reciprocal intercellular communication, whereas functional divergence is determined by the specific substrates modified within each cell type.

Different disease stimuli and pathological stages

Disease mechanisms can be analyzed across four dimensions: the recognition of receptors or danger signals, the kinetics of post-translational modification activation, the intensity of metabolic or proteostatic feedback, and the necessity for structural repair. LPS exemplifies a receptor-dominant response characterized by rapid synchronization. In BV2 microglia, phosphorylation events involving TAK1, IKK, and p65 are observable within approximately 15 minutes, with a marked reduction of IκBα by 30 minutes. Additionally, phosphorylation of p38 can initiate within 5 minutes, reach its peak around 30 minutes, and decrease significantly by 60 minutes [ 272 ]. Chromatin regulation does not necessarily experience a delay of several hours. In EOC13 microglial cells, LPS-induced acetylation of histones H3 and H4 at the CD40 promoter is detectable within approximately 30 minutes and persists for up to 2 hours, whereas the induction of CD40 mRNA is observed between 4 to 8 hours [ 273 ]. These temporal dynamics are contingent upon the specific model and dosage rather than being universally applicable. They delineate an early phase characterized by kinase activation and protein degradation from a subsequent phase involving promoter occupancy and transcriptional output.

Aβ and tau proteins share the activation of the MAPK/NF-κB pathway with LPS but differ in their receptor interactions and proteostatic feedback mechanisms. Fibrillar Aβ engages CD14, TLR2, and TLR4 receptors, leading to the activation of p38, the generation of ROS, and altered microglial phagocytosis [ 274 ]. In contrast, tau preformed fibrils preferentially activate the TLR2-MyD88 pathway rather than the TLR4-MyD88 pathway in the models cited [ 269 ]. Subsequently, microglial NF-κB modulates tau processing and release, establishing a feedback loop that facilitates tau seeding and neurotoxicity [ 270 ]. Unlike LPS, Aβ and tau serve both as inflammatory stimuli and as substrates for cellular uptake and degradation. The efficacy of inhibiting p38 or NF-κB is contingent not only upon the initiation of inflammation but also on the potential disruption of beneficial aggregate clearance.

Both ischemia and TBI exhibit rapid sterile-injury signals, such as extracellular ATP, ionic imbalance, ROS, mitochondrial damage, and NLRP3 activation. Ischemia further involves prolonged oxygen and nutrient deprivation, which is associated with VHL-dependent HIF-1α turnover, SIRT1 activity, SUMOylation, and lactate-dependent histone modification. The functional outcomes vary temporally and with different substrates: early global accumulation of SUMO2/3 may enhance stress tolerance, whereas subsequent substrate-specific deSUMOylation can either facilitate or inhibit inflammatory processes. Similarly, H3K18la is not uniformly pro-inflammatory; in an ischemic stroke model, increased microglial H3K18la enhances PLXNB2 expression and mitigates inflammation. TBI is characterized by additional mechanical and hemorrhagic signals, including barrier rupture, heme, TNF-α, and mixed cell-death pathways, which activate p38/JNK, NLRP3, ubiquitin ligases, and DUBs [ 275 ]. In a controlled cortical impact model, AKT-dependent phosphorylation is crucial for maintaining USP4 stability; USP4 subsequently deubiquitinated and stabilized ZBP1, thereby promoting microglial PANoptosis [ 276 ]. This establishes a specific kinase–DUB–substrate pathway that differentiates hemorrhagic TBI signaling from mere LPS stimulation. Nonetheless, this finding is model-specific and should not be extrapolated to encompass all severities or phases of TBI.

In contrast, demyelinating injury is characterized by a shift in therapeutic focus from inflammation suppression to myelin restoration. Early PTMs modulate microglial debris clearance and astrocytic responses, while later stages influence OPC proliferation, differentiation, and myelin synthesis. OPC mTOR signaling facilitates metabolic adaptation and early myelin production following cuprizone-induced demyelination, yet it exhibits no significant effect after focal lysophosphatidylcholine lesions, as reported in the referenced study [ 159 ]. SIRT1 offers another example of timing-dependent effects: its activation suppresses inflammatory transcription across various microglial and astrocytic systems, whereas SIRT1 inactivation enhances adult OPC expansion and promotes remyelination in specific demyelination models [ 172 ].

The kinetics of these processes have significant implications for therapeutic intervention. In an acute LPS model, inhibiting TAK1, IKK, or p38 prior to or within the first 15–30 minutes targets the initiation of inflammation, whereas intervention several hours later primarily affects sustained transcription rather than the initial phosphorylation pulse. In the context of demyelination, the same inhibitor may reduce early inflammation but hinder later oligodendrocyte precursor cell (OPC) differentiation. Consequently, there is no standardized temporal criterion for distinguishing between acute and chronic progression. Experimentally determining relevant time windows is essential for each specific stimulus, cell type, and substrate. Events occurring within the initial minutes are inadequately resolved by conventional sampling techniques, while persistent chromatin modifications may endure for days or weeks, contributing to inflammatory memory [ 277 ].

NF‑κB, NLRP3 and JAK-STAT signaling pathways

PTM crosstalk in neuroinflammation extends beyond interactions between pairs of modifications. Within the NF-κB, NLRP3, and JAK–STAT pathways, phosphorylation, ubiquitination, SUMOylation, and acetylation function in ordered or competitive combinations that govern signal initiation, amplification, nuclear transcription, and termination. These three pathways collectively constitute an interconnected signaling network regulated by PTMs, rather than functioning as three separate linear cascades.

Within the NF-κB pathway, PTMs operate in a sequential manner, progressing from receptor-proximal signaling complexes to nuclear transcriptional processes. Upon stimulation by LPS, amyloid-β, or α-synuclein, TLR-associated TRAF6 complexes are activated. In these complexes, K63-linked ubiquitin chains serve as signaling scaffolds facilitating the activation of TAK1 and IKK [ 278 ] (Fig. 5 ). The activated IKK subsequently phosphorylates IκBα at Ser32 and Ser36, creating a β-TrCP-binding phosphodegron that initiates K48-linked ubiquitination and the proteasomal degradation of IκBα [ 279 ]. Conversely, conjugation with SUMO1 at Lys21 can compete with ubiquitination, thereby stabilizing IκBα [ 280 ]. Consequently, the fate of IκBα is determined by the ordered sequence of phosphorylation and ubiquitination, as well as the competition between ubiquitin and SUMO at specific residues. Following the degradation of IκBα, the released p65 translocates into the nucleus, where phosphorylation at Ser536 enhances transcriptional competence, and acetylation at Lys310 supports full transcriptional activity and nuclear persistence. The SUMOylation of p65 or its associated coregulators can significantly influence promoter occupancy, the composition of transcriptional complexes, nuclear export, and protein turnover [ 53 , 281 ]. Consequently, the output of NF-κB is determined by the coordinated cytoplasmic degradation of IκBα and the combinatorial modification of nuclear p65, rather than solely by the abundance of nuclear p65.

The NLRP3 inflammasome integrates multiple PTMs during both its priming and activation phases. NF-κB-dependent priming enhances the expression of NLRP3 and pro-IL-1β, thereby establishing a connection between NF-κB signaling and inflammasome competence [ 282 , 283 ]. During activation, phosphorylation modulates the conformation, subcellular localization, and complex assembly of NLRP3. Although both protein kinase D and protein kinase A phosphorylate NLRP3 at Ser295, phosphorylation by protein kinase D facilitates NLRP3 redistribution and inflammasome assembly, whereas phosphorylation by protein kinase A inhibits its ATPase activity and limits activation [ 284 , 285 ]. Ubiquitination adds an additional layer of regulation. In macrophage-based systems, TRIM31 promotes K48-linked ubiquitination and proteasomal degradation of NLRP3, thereby restraining inflammasome activity [ 268 ]. USP7 and USP47 are also implicated in the activation of NLRP3 in macrophages. Pharmacological or combined genetic inhibition of these enzymes modifies NLRP3-containing oligomeric complexes, disrupts ASC oligomerization and speck formation, and diminishes IL-1β release [ 286 ]. Notably, inhibition of USP7/USP47 does not decrease the total abundance of NLRP3 protein, suggesting that these deubiquitinases do not simply stabilize NLRP3 by removing K48-linked degradative chains [ 286 ]. Within the central nervous system, functional activation of NLRP3 has been most consistently observed in microglia, whereas the cited models do not demonstrate similar functional activation in astrocytes [ 287 , 288 ]. Given that mechanistic studies of TRIM31, USP7, and USP47 have predominantly been conducted in macrophage-based systems, it remains to be determined whether these enzymes regulate glial NLRP3 through analogous mechanisms.

In the JAK-STAT signaling pathway, receptor-proximal phosphorylation is integrated with nuclear acetylation and ubiquitin-dependent negative feedback. The binding of IL-6, interferons, or IL-4/IL-13 to their respective receptors activates receptor-associated JAK kinases, leading to the phosphorylation of STAT3, STAT1, or STAT6, respectively [ 289 ]. Upon phosphorylation, STAT proteins dimerize and translocate to the nucleus (Fig. 5 ), where they play distinct roles: STAT1 is predominantly linked to inflammatory transcription, STAT6 facilitates anti-inflammatory and repair-associated processes, and STAT3 elicits context-dependent responses—ranging from inflammation and survival to tissue repair—based on upstream cytokine signals and the cellular environment [ 290 , 291 ]. STAT3 exemplifies the complexity of combinatorial PTM regulation: phosphorylation at Tyr705 enhances dimerization and nuclear localization, while p300-mediated acetylation at Lys685 stabilizes STAT3 dimers and transcriptional complexes [ 292 ]. Subsequently, nuclear SIRT1 deacetylates STAT3, thereby attenuating its transcriptional activity. Phosphorylation of SIRT1 at Tyr280 and Tyr301 by JAK1 does not impair SIRT1‘s catalytic function; rather, it enhances the interaction between SIRT1 and STAT3, promoting STAT3 deacetylation and establishing a negative feedback loop within the JAK1–STAT3 signaling axis [ 293 ]. Additionally, SOCS proteins act as a regulatory checkpoint by inhibiting receptor-associated JAKs and recruiting E3 ubiquitin ligase complexes to facilitate the ubiquitin-dependent degradation of pathway components [ 20 – 23 ]. The output of the JAK-STAT pathway is determined by a combination of STAT phosphorylation, STAT acetylation, SIRT1-mediated deacetylation, and SOCS-associated ubiquitination, rather than solely by STAT phosphorylation.

These pathways are interconnected through their spatial organization and shared inflammatory mediators. Receptor-proximal K63-linked ubiquitin scaffolds and kinase complexes initiate NF-κB signaling, while nuclear NF-κB provides a priming signal for NLRP3 and induces cytokines such as IL-6, which subsequently engage JAK-STAT signaling (Fig. 5 ). Mitochondrial dysfunction and ROS promote NLRP3 activation, whereas nuclear acetylation and deacetylation regulate the transcriptional outputs of both p65 and STAT3. The metabolic state can further modulate this network by altering mitochondrial ROS, acetyl-CoA availability, and the NAD + /NADH balance, thereby influencing NLRP3 activation, p65 and STAT3 acetylation, and SIRT1-dependent negative feedback mechanisms [ 294 , 295 ]. Consequently, NF-κB, NLRP3, and JAK-STAT pathways do not function as isolated entities but rather form an interconnected signaling network through cytokine release, inflammasome priming, and transcriptional feedback. Multiple PTMs collectively regulate the initiation, amplification, and resolution of inflammatory responses by modulating the activity, stability, subcellular trafficking, and complex assembly of key signaling proteins. The ultimate effects of these modifications are contingent upon the specific substrate and residue modified, subcellular localization, cellular state, and stage of disease. Therefore, it is imperative to evaluate these pathways by considering the dynamic coordination of multiple PTMs rather than relying solely on measurements of a single protein or modification. Such an integrated approach may yield a more accurate understanding of the magnitude, duration, and biological consequences of neuroinflammation.

Research hotspots and future perspectives

PTMs related therapeutic targets in neuroinflammation

In recent years, multiple PTMs have been identified as critical regulators of inflammatory responses in the CNS, including histone deacetylation, SUMO conjugation, O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, and ubiquitination. These modifications exert precise control over inflammatory gene transcription, inflammasome assembly, and cell death pathways, leading to the increasing recognition of their regulatory enzymes as viable therapeutic targets.

Along the acetylation axis, accumulating experimental evidence suggests that HDACs play a pivotal role in promoting the proinflammatory polarization of microglia and astrocytes [ 296 ]. In amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice, the administration of the selective class I HDAC inhibitor BG45 results in increased histone H3K9/14 acetylation within the hippocampus and entorhinal cortex, significantly reduces the expression of IL-1β, TNF-α, and other inflammatory mediators, attenuates glial activation, and ameliorates deficits in learning and memory [ 297 ]. Similarly, other HDAC inhibitors have been demonstrated to reverse astrocytic dysfunction and cognitive impairment induced by amyloid oligomers [ 298 ]. These findings endorse a strategy of cell type-specific HDAC inhibition to remodel chromatin acetylation and mitigate maladaptive inflammatory transcriptional programs.

The nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1 is considered a crucial negative regulator that links metabolic stress to inflammatory signaling [ 299 ]. Numerous ischemic stroke models indicate that the activation or overexpression of SIRT1 mitigates the proinflammatory polarization of microglia and astrocytes, suppresses the activity of the NLRP3 inflammasome and caspase-1, reduces the release of IL-1β and IL-18, and enhances long-term neurological recovery [ 300 , 301 ]. Concurrently, SIRT1 activation ameliorates the disruption of the BBB and the blood-spinal cord barrier (BSCB) following ischemia-reperfusion injury, partially by stabilizing tight junction proteins, limiting oxidative stress, and deacetylating NF-κB p65 [ 302 , 303 ]. Collectively, these findings propose that the combination of HDAC inhibition with SIRT1 activation at the acetylation level may offer a dual approach that selectively attenuates chronic detrimental inflammation while preserving essential immune functions.

Additionally, several emerging targets on the methylation and ubiquitination axes hold promise for modulating neuroinflammation. Notably, the histone methyltransferase EZH2, which catalyzes the trimethylation of H3K27, is significantly upregulated in microglia following neural injury and promotes the expression of proinflammatory genes and neuropathic pain [ 304 ]. DZNep has been shown to indirectly attenuate EZH2/H3K27me3 signaling and inhibit microglial activation following experimental ischemic stroke [ 305 ]. Additionally, Sigmoidin B has emerged as a potential EZH2 degrader, influencing the EZH2–AKT2 axis, altering microglial polarization, and mitigating neuroinflammation and cognitive deficits in models of sepsis-associated encephalopathy [ 306 ]. In the context of ubiquitination, the deubiquitinase USP7 has been identified as a stabilizer of various inflammatory signaling proteins, thereby exacerbating neuroinflammation [ 307 ]. Small molecule inhibitors that target non-catalytic domains of USP7 have demonstrated efficacy in significantly reducing microglial activation and inflammatory cytokine production in models of Parkinson’s disease and other neurodegenerative disorders, leading to improvements in motor and cognitive functions [ 307 ].

In summary, we have compiled and presented a selection of currently reported post-translational modification-related therapeutic agents (Table 2 ). Emerging evidence suggests that small-molecule inhibitors targeting deacetylases, the SUMOylation pathway, and the O-GlcNAc cycling mechanism consistently exhibit neuroprotective effects across a variety of neuroinflammation models. Nonetheless, the clinical translation of these findings is impeded by challenges such as limited target specificity, uncertain long-term safety, and the absence of stratification biomarkers based on PTMs. Future research must integrate refined molecular profiling with advanced drug delivery technologies to develop PTM-targeted interventions that are specific to defined cell types and disease stages.

Despite methodological advancements, PTM studies continue to face challenges such as low modification stoichiometry, rapid turnover, limited starting material, and sample loss during enrichment processes. Pre-analytical handling is of particular importance, as studies on tumor specimens have demonstrated that short post-excision ischemic intervals can rapidly alter stress-associated phosphorylation without corresponding changes in total protein abundance [ 326 ]. Although this evidence was obtained outside the nervous system, it underscores a general risk of tissue-handling artifacts that necessitates direct evaluation in neuroimmune samples. Furthermore, issues such as antibody cross-reactivity, incomplete or biased enrichment, uncertain site localization, and the inability of bulk brain-tissue analyses to resolve cellular heterogeneity further complicate data interpretation. Furthermore, the abundance of modified peptides does not inherently indicate site occupancy. To draw reliable conclusions, it is essential to employ rapid sample processing that preserves PTMs, conduct parallel quantification of the total proteome, ensure biological replication, utilize purified or spatially resolved cell populations, and perform orthogonal validation. Thus, the primary challenge is not solely the detection of candidate PTMs, but rather the translation of bulk or associative signals into cell-, site-, and time-specific causal mechanisms. This level of evidentiary rigor is particularly crucial when extrapolating findings from non-neural experimental systems to neuroimmune cells.

Construction of PTMs regulatory networks by single cell omics

To address the aforementioned controversies, it is essential to employ methodologies that provide both cell-state resolution and molecular specificity. Traditional transcriptomic and proteomic analyses have predominantly utilized bulk tissue samples or heterogeneous cell populations, resulting in the averaging of signals from diverse cell types and activation states. This methodological limitation hinders the ability to discern dynamic alterations in PTM landscapes within distinct cellular subsets and obstructs the precise identification of rare disease-associated subpopulations or stage-specific regulatory transitions.

Recent high-throughput investigations have demonstrated that, in neuroinflammatory conditions such as cerebral ischemia and Alzheimer’s disease, PTM-related regulatory patterns exhibit significant heterogeneity among glial and neuronal subpopulations. This heterogeneity is intricately associated with cell fate, the duration of inflammatory responses, and neuronal vulnerability [ 277 , 327 , 328 ].

The advent of single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) technologies has facilitated the reconstruction of comprehensive brain-wide maps of cellular lineages and activation states throughout the neuroinflammatory trajectory [ 329 ]. Numerous single-cell studies focusing on Alzheimer’s disease and ischemic stroke have identified a variety of subclasses of reactive astrocytes and disease-associated microglia. These subclasses exhibit signature genes that are enriched not only in inflammatory signaling and metabolic pathways but also in kinases, deacetylases, and other enzymes related to PTMs [ 330 – 332 ]. These datasets elucidate the spectrum of cellular states involved in neuroinflammation and provide a framework for inferring the activation patterns of various PTM axes at the transcriptional level.

However, transcriptomic data can only indirectly represent PTM regulation, and a comprehensive understanding of PTM networks necessitates single-cell omics analyses at the protein and chromatin levels. Single-cell multi-omics approaches, which simultaneously profile transcriptomes, epigenomes, and, in some instances, surface or intracellular proteins within the same cell, present a robust methodology for linking PTM enzymes with their substrates and subsequent transcriptional programs [ 333 ]. Integrative analyses of single-cell transcriptomic and epigenomic data derived from human brain samples have demonstrated that disease-associated glial states in neurodegenerative disorders frequently align with specific histone modification signatures and altered chromatin accessibility. These phenomena are closely linked to the expression of upstream PTM regulators [ 334 ].

At the epigenomic level, next-generation single-cell techniques such as Cleavage Under Targets and Tagmentation (CUT&Tag), along with its multi-omics derivatives, facilitate the simultaneous profiling of multiple histone marks and messenger RNA within individual cells. This allows for the parallel mapping of acetylation and methylation marks, such as H3K27ac and H3K27me3, in conjunction with transcriptional output [ 335 , 336 ]. These advanced technologies provide the opportunity to construct three-dimensional networks that interconnect histone PTMs, transcriptional programs, and cell states. In neuroinflammatory models, such methodologies are anticipated to differentiate combinations of pro-inflammatory and reparative chromatin marks across distinct glial subsets, thereby unveiling more cell-specific epigenetic drug targets.

Over the past three years, single-cell proteomics (SCP) utilizing mass spectrometry has achieved significant advancements in both sensitivity and throughput, enabling the quantification of thousands of proteins within individual cells [ 337 , 338 ]. When coupled with optimized sample preparation techniques and state-of-the-art mass spectrometers, SCP is capable of delineating the protein expression profiles of microglia, astrocytes, and brain endothelial cells within the context of the neuroinflammatory microenvironment. Although current methodologies for site-specific analysis of phosphorylation, acetylation, and ubiquitination at single-cell resolution are constrained by limitations in depth, coverage, and reproducibility, emerging workflows hold promise for overcoming these challenges. By integrating these proteomic data with upstream single-cell transcriptomic and epigenomic information, it is anticipated that researchers will be able to reconstruct PTM regulatory networks with unprecedented resolution.

Despite recent advancements in achieving comprehensive single-cell total-proteome coverage [ 337 , 338 ], the in-depth and reproducible profiling of site-specific PTMs in individual neuroimmune cells remains a significant technical challenge. Techniques such as single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) are capable of identifying candidate PTM enzymes and PTM-related pathways at the transcriptomic level; however, they do not provide direct evidence of specific protein residue modifications. Direct PTM analysis necessitates alignment with the specific chemistry of the modification. For instance, phosphopeptides are typically enriched using immobilized metal-affinity chromatography or titanium dioxide (TiO₂) prior to liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis [ 339 , 340 ]. Ubiquitination can be assessed through K-ε-GG remnant immunoaffinity profiling at the acceptor-site level or through the use of tandem ubiquitin-binding entities for intact polyubiquitinated proteins [ 341 , 342 ]. Lysine acetylation is profiled via immunoaffinity enrichment, whereas histone lactylation is examined through histone extraction followed by site-specific mass spectrometry analysis [ 343 , 344 ]. SUMOylation sites are identified using protease-assisted enrichment strategies such as PRISM [ 345 ], and S-nitrosylated proteins along with cysteine sites are captured using biotin-switch-derived or SNO-RAC workflows [ 346 ]. These approaches are complementary rather than interchangeable: enrichment-based mass spectrometry facilitates the discovery of PTMs and site assignment, whereas targeted mass spectrometry or rigorously validated site-specific antibodies are more suitable for confirming specific changes.

It is important to differentiate between methodological evidence and mechanistic evidence. Alterations in enriched modified peptides should be interpreted in conjunction with the corresponding total proteome, as they may indicate changes in protein abundance rather than modification occupancy. Accurate estimation of site occupancy necessitates the measurement of both the modified peptide and its corresponding unmodified peptide. Similarly, co-immunoprecipitation demonstrates protein association but does not confirm direct modification between proteins. A direct writer/eraser–substrate relationship is most convincingly demonstrated through enzyme perturbation using wild-type and catalytically inactive controls, in vitro reconstitution with purified components, loss of modification in a site-mutant substrate, and functional rescue experiments. Thus, changes at the transcript level, protein interactions, site-specific modifications, and functional causality represent distinct and increasingly robust tiers of evidence.

Crosstalk between metabolism and PTMs

Under neuroinflammatory conditions, cellular metabolic reprogramming and PTMs are intricately and reciprocally linked. Enhanced glycolysis, modifications in the tricarboxylic acid (TCA) cycle, and variations in lipid metabolism not only provide energy and biosynthetic precursors for activated microglia and astrocytes but also produce metabolic intermediates such as lactate, acetyl-CoA, and succinyl coenzyme A (succinyl-CoA), which directly facilitate specific PTMs [ 8 , 295 , 347 ]. Single-cell and multi-omics studies in neurodegenerative diseases have demonstrated that microglial shifts towards glycolysis, mitochondrial dysfunction, and lipid accumulation frequently coincide with characteristic alterations in PTM enzyme expression and modification sites, suggesting that metabolism-sensing PTMs are critical components of neuroinflammatory regulation [ 348 , 349 ].

Lysine lactylation represents a metabolism-linked PTM influenced by lactate availability, capable of altering both histone and non-histone lysine residues. The functional outcomes of this modification are contingent upon the specific substrate, cell type, and pathological context. In a murine model of ischemic stroke, increased lactylation of microglial H3K18 was observed to upregulate PLXNB2 expression, promote an anti-inflammatory microenvironment, and mitigate neurological damage [ 275 , 350 ]. Similarly, in mice treated with AlCl₃/D-gal, enhancements in histone H3 lactylation, whether induced by exercise or lactate, facilitated an anti-inflammatory and reparative microglial phenotype, subsequently improving cognitive dysfunction [ 351 ]. These observations suggest a context-dependent protective role for microglial histone lactylation within the examined models; however, they do not substantiate a universal biphasic effect across various neuroinflammatory conditions. In contrast, succinylation is another metabolism-related PTM associated with mitochondrial function and succinyl-CoA availability. In BV2 cells treated with LPS, CPT1A was found to promote the succinylation of VDR at K117, thereby enhancing VDR stability and reducing microglia-mediated inflammatory responses [ 352 ]. Lysine succinylation serves as a precise indicator of mitochondrial TCA cycle activity and intracellular succinyl-CoA concentrations, frequently correlating with mitochondrial damage in microglia and the emergence of senescent phenotypes within neuroinflammatory environments [ 295 ]. Recent research suggests that elevated protein succinylation in the brain may propel microglia toward a senescent state, thereby enhancing their inflammatory secretory functions. Strategies such as manipulating fatty acid beta-oxidation via carnitine palmitoyltransferase 1A (CPT1A) and modulating the succinylation of the vitamin D receptor (VDR) have been proposed to reprogram microglial metabolism and inflammatory responses, potentially mitigating neuroinflammation and neurodegenerative diseases.

Within the realm of lipid metabolism, palmitoylation involves the reversible attachment of long-chain fatty acids to cysteine residues on intracellular proteins, thereby influencing the localization and residence time of receptors and signaling proteins within lipid raft microdomains [ 353 ]. Research in the nervous system indicates that dysregulated protein palmitoylation contributes to astrocyte activation and the release of inflammatory mediators. For instance, the palmitoylation of GFAP, facilitated by the palmitoyl acyltransferase ZDHHC23, augments spinal glial reactivity and stimulates the secretion of IL-6, CXCL10, and associated mediators, thereby constituting a significant mechanism underlying neuropathic pain and inflammatory amplification [ 354 ]. Crotonylation, a short-chain lysine acylation modulated by crotonyl coenzyme A (crotonyl-CoA), which is derived from fatty acid and amino acid metabolism, has been demonstrated to play crucial roles in neurogenesis, synaptic plasticity, and the tumor immune microenvironment [ 355 , 356 ]. Histone crotonylation has been implicated as an active epigenetic mark that regulates genes involved in metabolism and proliferation during neural stem cell fate determination and hippocampal memory formation [ 357 ]. Concurrently, analyses of gliomas and immune-related gene signatures indicate that crotonylation-associated genes and long non-coding RNAs are intricately linked to immune cell infiltration and therapeutic responses [ 358 ]. In conjunction with evidence from the broader field of immunology indicating that crotonylation of transcription factors, such as NF-κB, facilitates chronic inflammatory transcription [ 359 ], these findings suggest that crotonylation may serve as a link between metabolic reprogramming and immune transcriptional responses in neuroinflammatory conditions.

Furthermore, a growing body of research is investigating emerging metabolism-dependent PTMs (Table 3 ). These modifications, including lactylation, succinylation, palmitoylation, and crotonylation, are responsive to key metabolites such as lactate and succinyl-CoA, thereby integrating cellular energy status with chromatin architecture and the function of signaling proteins. In microglia and astrocytes, these modifications contribute to the establishment of finely tuned regulatory networks that connect metabolism, inflammatory responses, blood-brain barrier homeostasis, and neuronal survival. Consequently, they offer novel conceptual and therapeutic avenues for the metabolic epigenetic regulation of neuroinflammation.

Conclusion

Neuroinflammation represents a prevalent pathological feature across a range of CNS disorders, with disease outcomes being significantly influenced by the temporal activation patterns of microglia, astrocytes, oligodendrocytes, and infiltrating peripheral immune cells. PTMs play a crucial role in fine-tuning the functional polarization of these cells towards either pro-inflammatory or anti-inflammatory states, as well as towards injury-promoting or reparative states, by modulating receptors and key signaling pathways such as NF-κB, NLRP3, and JAK-STAT. Classical PTMs, including ubiquitination, SUMOylation, phosphorylation, acetylation, and methylation, along with metabolism-dependent modifications, constitute a complex regulatory network that influences myelin homeostasis and either maintains or disrupts the integrity of the neurovascular unit. Nevertheless, several challenges remain before these insights can be effectively translated into precision therapies. The functional consequences of PTMs are often dependent on specific sites, substrates, cell types, and developmental stages, and the robustness of evidence varies across CNS-resident and peripheral immune compartments. Furthermore, the widespread expression of numerous PTM-related enzymes poses challenges related to systemic toxicity, delivery across the blood-brain barrier, and off-target effects. Consequently, future advancements will rely not only on single-cell and spatial multi-omics, single-cell proteomics, and site-specific PTM mapping, but also on stringent cross-cell validation and biomarker-guided stratification. Therapeutic approaches that incorporate selective targeting of PTM enzymes with brain-specific delivery and strategically designed immune-metabolic combination regimens may ultimately facilitate more precise and safer interventions in specific neuroinflammatory subtypes.

Acknowledgements

None.

Abbreviations

TNFAIP3 (Tumor necrosis factor alpha-induced protein 3)

Acetyl coenzyme A

Alzheimer’s disease

Protein kinase B

Annexin A1

Activator protein 1

Apoptosis-associated speck-like protein containing a CARD

ASC inflammasome speck

Alpha-tubulin acetyltransferase 1

Activating transcription factor 2

Amyloid beta

Blood-brain barrier

Brain-derived neurotrophic factor

Complement component 1q

Cellular inhibitor of apoptosis proteins

Central nervous system

Cylindromatosis tumor suppressor protein

Deubiquitinases

Ubiquitin-activating enzyme

Ubiquitin-conjugating enzyme

Ubiquitin ligase

Endothelial PAS domain protein 1

Endoplasmic reticulum

Endoplasmic reticulum-associated degradation

Enhancer of zeste homolog 2

Gamma-activated sequence

Glial cell line-derived neurotrophic factor

Glial fibrillary acidic protein

Histone H3 lysine 27 trimethylation

Histone acetyltransferases

Histone deacetylase 6

Histone deacetylases

Hypoxia-inducible factor 1 alpha

Interferon gamma

IκB kinase

Interleukin-10

Interleukin-18

Interleukin-1 beta

Interleukin-6

Inducible nitric oxide synthase

Ischemic stroke

Interferon-stimulated response element

Inhibitor of nuclear factor kappa-B alpha

c-Jun N-terminal kinase

Lysine 48-linked ubiquitin chain

Lysine 63-linked ubiquitin chain

Lethal (3) malignant brain tumor-like protein 3

Lipopolysaccharide

Linear ubiquitin chain assembly complex

Mitogen-activated protein kinase

Membrane-associated RING-CH protein 2

Myelin basic protein

Multiple sclerosis

Neurodegenerative disorders

Nuclear factor kappa B

NOD-like receptor protein 3

Nuclear receptor subfamily 4 group A member 1

O-linked N-acetylglucosamine

Oligodendrocytes

Oligodendrocyte precursor cells

OTU domain-containing ubiquitin aldehyde-binding protein 1

OTU deubiquitinase with linear linkage specificity

Parkinson’s disease

Prolyl hydroxylase domain-containing protein

Proteolipid protein

Polycomb repressive complex 2

Post-translational modifications

Really interesting new gene

Reactive oxygen species

Suberoylanilide hydroxamic acid

Sentrin/SUMO-specific proteases

SUMO-interacting motifs

Sirtuin 1

S-nitrosylation

Suppressor of cytokine signaling

SRY-box transcription factor 10

Signal transducer and activator of transcription

Signal transducer and activator of transcription 1

Signal transducer and activator of transcription 3

Succinylation

Small ubiquitin-like modifier

Small ubiquitin-like modifier 2/3

Small ubiquitin-like modifier conjugation

Transforming growth factor β-activated kinase 1

Traumatic brain injury

Toll-like receptors

Tumor necrosis factor alpha

TNF receptor-associated factor 6

Ubiquitin

Unc-51-like kinase 1

Unfolded protein response

Ubiquitin-specific protease

Vascular endothelial growth factor

Von Hippel-Lindau tumor suppressor

Author contributions

W.L., Y.L., H.Z., H.Z., W.Z. contributed to the manuscript writing and figure preparation, T.H. and X.K. designed the work, W.S., W.L. and X.K. supervised the work. All authors have read and approved the article.

Funding

This work was supported by grants from the Key Research and Development Project of Henan Province (251111314400).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable. This manuscript does not contain any studies with human participants or animals performed by any of the authors.

Consent for publication

Not applicable. This manuscript does not include details, images, or videos relating to an individual person.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Wei Li and Yaqi Liu contributed equally to this work.

Contributor Information

Ting Hu, Email: huting@smmu.edu.cn.

Yan Liao, Email: liaoyan001128@163.com.

Wangzheqi Zhang, Email: zwzq001031@smmu.edu.cn.

Xiaohong Kang, Email: 1fy2014036@xxmu.edu.cn.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.