NLRP3 Inflammasome Activation in Oxidative Stress: A Key Mechanism Driving Neuroinflammation

Abstract

Background

In acquired and neurodegenerative brain diseases, inflammation-mediated neuronal death contributes to the deterioration of neurological deficits in patients. In the innate immune system, the NLRP3 inflammasome is a cytosolic complex that regulates the release of proinflammatory cytokines IL-1β and IL-18, thereby amplifying the inflammatory response and neuronal damage. Consequently, inhibition of the NLRP3 inflammasome represents a promising pharmacological strategy to limit inflammation across multiple pathologies. Oxidative stress is a common hallmark of these pathological conditions that contribute to neuronal death and influence NLRP3 activation. Despite the implications of these events, the molecular mechanisms underlying this activation remain poorly understood.

Summary

In this review, we describe the key features of the NLRP3 inflammasome and explore the role of oxidative stress in its activation. Additionally, we discuss the evidence supporting the regulation of inflammasome activity by antioxidant molecules.

Key Message

Understanding the role of oxidative stress in NLRP3-mediated inflammation offers promising advantages for therapeutic strategies to reduce neuronal death.

Introduction

Neuroinflammation is a hallmark of many neurodegenerative diseases, such as those caused by trauma, tumors, ischemia, metabolic imbalances, toxins, infections, developmental issues, or degenerative processes, which are characterized by both direct and indirect neuroinflammation driven by immune system activity [1]. It involves the activation of innate immune responses within the central nervous system (CNS), primarily mediated by glial cells such as microglia and astrocytes [2]. While acute neuroinflammation can be protective and facilitate tissue repair, chronic neuroinflammation has been associated with neuronal damage and disease progression [3].

Inflammatory response is closely linked to oxidative stress, a condition characterized by an imbalance between the production of reactive oxygen species (ROS) and the capacity of antioxidant defenses to neutralize them [4]. Elevated ROS levels within the neural tissue can result from mitochondrial dysfunction, environmental toxins, aging, and genetic predisposition [5]. These reactive molecules can directly damage cellular components, including lipids, proteins, and nucleic acids, impairing cellular functions and promoting cell death [6]. Moreover, oxidative stress acts as a signaling mediator that amplifies inflammatory responses through the activation of various intracellular pathways.

An important regulator of neuroinflammation is the NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome. This multiprotein complex functions as a sensor for cellular stress signals, including those induced by oxidative damage [7]. Upon activation, NLRP3 assembles with adaptor proteins procaspase-1 to facilitate caspase 1 activation, leading to the maturation and release of the proinflammatory cytokines IL-1β and IL-18 [8]. These cytokines promote further activation of neural cells and recruitment of peripheral immune cells, sustaining the inflammatory cycle. Recent research has shown oxidative stress production by NLRP3 inflammasome activation in the rat brain [9]. On the other hand, experimental evidence suggests that ROS generation, mitochondrial dysfunction, and oxidative damage to cellular components serve as potent triggers for NLRP3 activation; this connection between redox imbalance and the inflammatory process highlights novel therapeutic targets aimed at modulating both oxidative stress and inflammasome activity [10]. In this review, we explore the mechanisms by which oxidative stress influences NLRP3 inflammasome activation in the brain, emphasizing its implications for neuroinflammatory diseases.

Oxidative Stress in the Brain

The CNS is particularly susceptible to oxidative stress due to its high metabolic rate, abundant lipid content, and low antioxidant capacity [11]. Neurons rely on mitochondrial oxidative phosphorylation for ATP production, a process that generates ROS as byproducts. Mitochondria are one of the primary sources of ROS in neurons, where electron leakage from the electron transport chain results in superoxide anion formation [12]. During vigorous oxidative metabolism, mitochondria produce and accumulate ROS, with about 1–2% of the oxygen consumed by cells during normal respiration being transformed into these reactive molecules [13]. Another major source of ROS is NADPH oxidases (NOXs), an enzymatic system that generates ROS in a regulated manner for signaling purposes and produces significant amounts under inflammatory and pathological conditions [14]. In addition, enzymatic complexes such as xanthine oxidases and cyclooxygenases (COXs) contribute to ROS production, particularly during inflammatory responses [14]. Under physiological conditions, ROS serves essential functions in cellular signaling and neuroplasticity; however, an imbalance favoring ROS accumulation can lead to oxidative damage of lipids, proteins, and DNA [13].

Neurons are especially vulnerable to oxidative damage due to their high metabolic demands and the abundance of polyunsaturated fatty acids, which are susceptible to peroxidation [15]. Additionally, mitochondrial dysfunction caused by genetic mutations, environmental toxins, or aging exacerbates the production of ROS [11]. Excessive generation of reactive oxygen and nitrogen species, coupled with deficiencies in antioxidant defenses, protein oligomerization, cytokine release, inflammatory responses, blood-brain barrier (BBB) abnormalities, and proteasome system dysfunction, collectively further compromise cellular integrity and function. [16]. Some environmental factors such as exposure to neurotoxins, heavy metals, pesticides, radiation, and pollutants can increase ROS generation or impair antioxidant systems [17].

Oxidative stress leads to various detrimental effects in neural cells. Including lipid peroxidation, which damages the neuronal membranes and impairs cell integrity and signaling [18]. Protein oxidation, which alters enzyme activity and receptor function, induces the disruption of neural communication. Moreover, DNA damage resulting from oxidative lesions on genetic material can lead to mutations and apoptosis [19]. These factors collectively create a conducive environment to oxidative injury, which can precipitate or accelerate neurodegenerative processes.

Neural cells use a variety of antioxidant systems to neutralize ROS, including enzymatic antioxidants such as catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH) peroxidase, as well as non-enzymatic molecules such as GSH, vitamin C, and vitamin E [20]. Accumulating evidence indicates that oxidative stress is not merely a consequence of neurodegeneration but also actively contributes to the initiation and progression of neural damage [21, 22].

Sources of Oxidative Damage

Oxidative damage in biological systems originates from a variety of endogenous and exogenous sources, which contribute to the accumulation of ROS and reactive nitrogen species (RNS) [23]. As mentioned previously, mitochondrial respiration represents a major intrinsic source of ROS, including superoxide anion, hydrogen peroxide, and hydroxyl radicals, produced through electron leakage in the electron transport chain and regulated by enzymes such as Mn-SOD and Cu/Zn-SOD [4]. Additionally, enzymatic systems actively generate ROS as part of their physiological functions. NOX, a family of membrane-bound enzymes, produce superoxide as a response to various stimuli, including inflammatory signals [24]. Xanthine oxidase catalyzes purine degradation, releasing ROS during metabolic processes, especially under ischemic or hypoxic conditions. COX involved in prostaglandin synthesis also produce ROS as byproducts. Other enzymes that catalyze ROS-generating chemical reactions are peroxidases, lipoxygenases, glucose oxidase, myeloperoxidase (MPO), and nitric oxide synthase [25]. These endogenous sources are tightly regulated under normal conditions; however, disruptions in mitochondrial function or enzyme activity can lead to excessive ROS production. These enzymatic sources are often upregulated during pathological states, amplifying oxidative stress and cellular injury [23].

Exogenous factors also play a significant role in inducing oxidative damage, especially when exposure is chronic or intense. Exposure to environmental pollutants, including heavy metals such as mercury and lead, cigarette smoke, ultraviolet radiation, and toxins such as pesticides, increases ROS production either directly or indirectly by disrupting cellular redox balance [26]. For example, exposure to heavy metals frequently induces the generation of free radicals through Fenton-like reactions, thereby elevating oxidative stress and resulting in the degradation of biological macromolecules, DNA damage, and various other harmful effects [27]. Dietary components, including certain toxins and pro-oxidant compounds, can further exacerbate oxidative stress when consumed in excess [28]. Additionally, lifestyle factors such as chronic stress and exposure to radiation can contribute to increased ROS levels. These external influences not only elevate oxidative burden but may also impair cellular repair mechanisms, making tissues more susceptible to oxidative injury over time [4].

The interplay between these internal and external sources underscores the multifaceted nature of oxidative damage. When the generation of ROS exceeds the capacity of antioxidant systems to neutralize them, oxidative modifications of lipids, proteins, and DNA occur, leading to cellular dysfunction and contributing to the development of pathologies [29].

Molecular Markers of Oxidative Stress

Molecular markers of oxidative stress serve as crucial indicators of cellular redox status and damage caused by ROS. These biomarkers typically reflect oxidative modifications of biomolecules such as lipids, proteins, and nucleic acids, providing insight into the underlying biochemical alterations [30]. Lipid peroxidation is a hallmark of oxidative damage in cell membranes, resulting from ROS attacking polyunsaturated fatty acids [31]. Malondialdehyde and 4-hydroxynonenal (4-HNE) are among the most extensively studied byproducts of lipid peroxidation. Elevated levels of these aldehydes are indicative of heightened oxidative stress and membrane lipid damage, often correlating with disease severity in neurodegenerative and cardiovascular conditions [32, 33]. Malondialdehyde can be quantified through the thiobarbituric acid reactive substances assay, while 4-HNE adducts can be detected via immunohistochemistry, confocal immunofluorescence (IF), or mass spectrometry [34, 35].

Nucleic acid oxidation, specifically the formation of 8-hydroxy-2′-deoxyguanosine (8-OHdG), functions as a specific marker of oxidative DNA damage. Measurement of 8-OHdG levels in gray (gy) tissue or circulating bodily fluids provides an assessment of oxidative genotoxicity [36]. Elevated levels of 8-OHdG are indicative of increased oxidative stress and are associated with mutagenesis and carcinogenesis. Quantification of 8-OHdG can be performed using several methodologies, including analytical high-performance liquid chromatography (HPLC), liquid chromatography-tandem mass spectrometry, or immunological assays such as HPLC (ELISA), IF, and automated immunofluorescence (AKLIDES) [37]. Similarly, RNA oxidative modifications, although less studied, are gaining attention due to their potential role in post-transcriptional regulation and cellular dysfunction. Quantifying these markers through techniques such as HPLC and ELISA aids in elucidating the extent of oxidative genetic injury [38]. Collectively, these molecular markers provide a comprehensive assessment of oxidative damage at both the cellular and molecular levels, thereby facilitating the identification of oxidative stress-related pathologies and the evaluation of therapeutic interventions aimed at mitigating oxidative injury [39].

Moreover, proteins are also susceptible to oxidative modifications, which can impair their function and contribute to cellular dysfunction. Common markers of protein oxidation include carbonyl groups introduced into amino acid side chains, which can be detected using spectrophotometric or immunoblotting techniques and serve as sensitive markers for protein damage and dysfunction [40]. Additionally, the formation of 3-nitrotyrosine implies nitrative stress, reflecting the interaction of ROS with RNS [41]. These oxidative modifications can disrupt enzymatic activities, promote protein aggregation, and initiate cellular signaling pathways associated with apoptosis and inflammation [42].

In addition to damage-specific markers, the activity levels of endogenous antioxidant enzymes such as SOD, CAT, thioredoxin (TRX), and GSH peroxidases can serve as indirect indicators of oxidative stress [43]. Alterations in the activity or expression levels of these enzymes often reflect adaptive responses or deficiencies that predispose tissues to oxidative injury [44]. Furthermore, measuring levels of reduced and oxidized glutathione (GSH/GSSG ratio) provides insights into the cellular redox environment [45]. Declines in antioxidant enzyme activity or shifts in redox couples are associated with increased oxidative damage and are useful for assessing the oxidative status within tissues [46]. Furthermore, levels of non-enzymatic antioxidants, including reduced GSH and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others), are measured to assess the overall antioxidant capacity [44].

Inflammatory Responses in Brain Pathologies

Inflammation is an innate immune response to infections, toxins, and injuries, aimed at limiting damage and facilitating repair. This process is mediated by cytokines, chemokines, ROS, and secondary messengers released by microglia, astrocytes, immune cells, and endothelial cells [47]. The extent of the inflammatory response varies depending on multiple factors and determines whether its effects are beneficial or detrimental. The intensity and duration of inflammation influence the nature of its impact on the brain. Typically, transient and low-grade inflammation supports brain health by promoting tissue repair, plasticity, and neuroprotection. Conversely, sustained and high-grade inflammation is associated with neuronal damage, impaired plasticity, and neurodegeneration, as observed in traumatic brain injury (TBI), stroke, and neurodegenerative diseases [47].

In the context of neuroinflammation, microglia play a central role in regulating inflammatory responses and maintaining homeostasis within the brain. These cells adopt distinct phenotypes depending on the physiological or pathological state. Factors such as lipopolysaccharide (LPS), interferon-gamma (IFN-γ), or α-synuclein stimulate microglia to adopt a proinflammatory phenotype. Proinflammatory microglia release cytokines like IL-1β, TNF-α, as well as ROS and inducible nitric oxide synthase, amplifying inflammatory responses that can lead to neuronal death. Conversely, mediators such as transforming growth factor-beta (TGF-β), IL-4, and IL-10 promote the transition from the proinflammatory to the anti-inflammatory phenotype. Anti-inflammatory microglia facilitate phagocytosis and extracellular matrix remodeling and support neuronal survival [48].

Several innate immune complexes regulate cytokine production and release by microglia, playing crucial roles in protective responses to pathogens and cellular damage. However, when these regulatory molecules become dysregulated or persistently activated, they can contribute to neuronal injury and degeneration. Among these complexes, the NLRP3 inflammasome stands out due to its significant involvement in the development of various acquired and neurodegenerative brain disorders [49].

NLRP3 Inflammasome: Structure and Function

The primary function of the NLRP3 inflammasome is to initiate and amplify inflammatory responses by promoting the maturation of cytokines that orchestrate immune defense [50] that play a vital role in recruiting immune cells, enhancing phagocytosis, and mediating tissue repair [51]. It represents a critical component of the innate immune system that detects a wide range of pathogenic and endogenous danger signals [52]. While predominantly found in the cytoplasm of immune cells such as macrophages, monocytes, neutrophils, and T cells, the NLRP3 inflammasome has also been identified in epithelial and skeletal muscle cells [53]. In the brain, the inflammasome is expressed in microglia, neurons, and astrocytes [54, 55]. It belongs to the family of pattern recognition receptors (PRRs), known as NLRs, which initiate inflammatory responses [56].

The NLRP3 inflammasome is a multi-protein complex that consists of three elements: the sensor protein NLRP3, the adaptor apoptosis-associated speck-like protein containing a CARD (ASC), and the effector caspase-1 [52]. The NLRP3 protein comprises three domains: an N-terminal pyrin domain (PYD) mediating interactions with ASC; a NACHT domain containing a nucleotide-binding domain (NBD), helical domains, and a winged helix domain essential for oligomerization; and a C-terminal leucine-rich repeat (LRR) domain involved in ligand recognition and autoinhibition through folding onto the NBD [57, 58]. Caspase-1, synthesized as an inactive zymogen, facilitates the maturation of pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into active cytokines through proteolytic cleavage [59] (Fig. 1).

Fig. 1.

Structure and activation of the NLRP3 inflammasome complex in responses to DAMPs and PAMPs. Demonstrates the assembly of the NLRP3 inflammasome complex, comprising the NLRP3 sensor protein, the ASC adaptor protein (apoptosis-associated speck-like protein containing a CARD), and pro-caspase-1, essential for innate immune response activation. After detection of DAMPs and PAMPs, such as lipopolysaccharide (LPS) or IL-1β by the Toll‐like receptor (TLR) and interleukin‐1 receptor (IL‐1R), respectively, the signalling pathway activates NF-κB, which triggers transcriptional activation of the proinflammatory cytokines pro-IL-1β and pro-IL-18 as well as NLRP3. The NLRP3 inflammasome assembles in response to stimuli such as ATP, mitochondrial dysfunction, potassium efflux, calcium influx, and lysosomal destabilization. Its activation triggers caspase-1 activation, leading to the proteolytic maturation of proinflammatory cytokines IL-1β and IL-18, thereby mediating inflammatory responses. Activation of the NLRP3 inflammasome induces pyroptosis, a highly inflammatory form of programmed cell death characterized by cellular swelling, cleavage of gasdermin D (GSDMD), formation of membrane pores, and subsequent release of proinflammatory cytokines IL-1β and IL-18, contributing to innate immune responses. Created in BioRender. Torres, A. (2026) https://BioRender.com/m4kosze.

Activation of the NLRP3 inflammasome involves a complex process triggered by various stimuli, such as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). These stimuli often induce cellular stress signals like potassium efflux, calcium flux, lysosomal disruption, mitochondrial dysfunction, ROS derived from mitochondria and NOX2, re-localization of cardiolipin to the outer mitochondrial membrane, and the release of oxidized mtDNA (Ox-mtDNA) [58]. These signals promote conformational changes in NLRP3, leading to its oligomerization and subsequent recruitment of ASC and caspase-1 [60]. This assembly results in the autocatalytic activation of caspase-1, which cleaves pro-IL-1β and pro-IL-18 and also promotes pyroptosis by releasing N-terminal fragments of gasdermin D (GSDMD), which oligomerize to form membrane pores that enable the release of IL-1β and IL-18 and permit the influx of water, leading to cell swelling and rupture [61].

Structural analyses of the NLRP3 inflammasome have revealed its intricate architecture, composed of three primary elements: the sensor molecule NLRP3 itself, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), and the effector enzyme caspase-1 [50]. NLRP3 features a central NBD (NACHT), a C-terminal LRR domain responsible for sensing danger signals, and an N-terminal PYD that mediates protein-protein interactions [62]. ATP exhibits a high binding affinity with the NLRP3 NATCH domain, which is essential for the self-oligomerization of NLRP3. The Walker A, B, and extended Walker B motifs are the main sites responsible for ATP binding within the NACHT domain [63]. There is evidence suggesting that the conformation of NLRP3 may be modulated through interactions with cochaperone proteins such as Hsp90 and SGT1, which play essential roles in its activation [64]. ASC acts as a bridge, linking NLRP3 to caspase-1 through PYD-PYD interactions, enabling caspase-1 activation [8]. Through the conformational change between the PYD and the NACHT domain, including a linker region (91–132 aa) and a short domain named FISNA (fish-specific NACHT associated, 135–208 aa) [65]. The precise assembly of these components is essential for the initiation of downstream inflammatory responses.

Given its central role in inflammation, NLRP3 inflammasome activity is tightly regulated at multiple levels, including ribosome stalling, transcriptional control, post-translational modifications (PTMs) of NLRP3 such as phosphorylation and ubiquitination, and the action of inhibitory proteins [66]. Factors such as cellular metabolic state, ion fluxes, and mitochondrial integrity influence its activation threshold. Understanding these regulatory mechanisms offers a potential opportunity for therapeutic intervention in diseases characterized by excessive inflammasome activation [63]. Pharmacological targeting of NLRP3 or its downstream signaling pathways is an active area of research, aiming to develop treatments for conditions ranging from metabolic disorders to neurodegenerative diseases [62].

Molecular Pathways of NLRP3 Activation

The NLRP3 inflammasome activation pathways comprise the canonical, noncanonical, and alternative pathways that are responsible for recognizing pathogens and danger signals, which subsequently trigger innate immune responses and pyroptosis [50]. Numerous pathogenic and danger stimuli can activate the canonical NLRP3 inflammasome through convergent upstream pathways that typically involve ionic fluxes (e.g., potassium efflux), mitochondrial dysfunction, and the production of ROS [67]. Reduction of intracellular potassium is a crucial mechanism in NLRP3 inflammasome activation. This serves as a common signal triggered by various NLRP3 agonists, such as nigericin, pore-forming toxins, ATP via P2X7 receptor activation, and particulate matter [68]. This efflux induces conformational changes in NLRP3 or related proteins, facilitating inflammasome assembly. Mitochondrial damage and the subsequent release of mitochondrial DNA and ROS act as additional signals that potentiate inflammasome assembly [69]. These mechanisms collectively serve as cellular danger signals, alerting the immune system to potential threats.

The noncanonical NLRP3 inflammasome pathway is activated by detection of cytoplasmic LPS, primarily via caspase-4 and caspase-5 in humans, resulting in gasdermin D cleavage and the induction of pyroptosis [70, 71]. Alternative inflammasome pathways bypass the priming step and are activated through TLR4 engagement by extracellular LPS, involving TIR domain-containing adapter-inducing interferon-β (TRIF) and caspase-8, independently of potassium efflux, ASC speck formation, or pyroptosis. This mechanism appears to be specific to NLRP3 activation in monocytes [72].

The activation of the NLRP3 inflammasome is a two-step process, with the initial “priming phase” being essential for its activation. During priming, PRRs, such as Toll-like receptors (TLRs), NLRs (NOD1 and NOD2), or cytokine receptors, recognize microbial components or endogenous signals, thereby activating nuclear factor kappa B (NF-κB) [73, 74]. NF-κB upregulates the transcription of NLRP3, pro-IL-1β, and pro-IL-18; however, basal NLRP3 levels are insufficient for inflammasome activation, and pro-IL-1β is not constitutively expressed in resting macrophages, whereas priming signals do not significantly alter the expression levels of ASC, pro-caspase-1, or pro-IL-18 [69, 75]. Additionally, MyD88 and TRIF, key adaptors in the NF-κB pathway, modulate NLRP3 and pro-IL-1β expression upon TLR activation [76]. While caspase-8 and FADD, though primarily associated with apoptosis, are also crucial for NLRP3 induction during priming, functioning independently of their apoptotic roles [77]. Caspase-8 engages with the IKK complex to enhance NF-κB activation, supporting its transcriptional activity and nuclear translocation. FADD plays a dual role in NF-κB signaling by both facilitating activation and repressing it through the induction of apoptosis [78].

A CRISPR genome-wide screen identified NEK7 as a key regulator of NLRP3 inflammasome activation. While previously known for its role in cell division, NEK7 acts as a molecular switch balancing mitosis and inflammasome activity in macrophages. Activation involves priming with LPS, which increases NLRP3-NEK7 interaction through electrostatic attraction, leading to NLRP3 oligomerization, recruitment of ASC, formation of the inflammasome complex, and pro-caspase-1 activation. NEK7 is essential for stabilizing these interactions within the inflammasome [79]. Priming thus establishes the necessary molecular groundwork by increasing the availability of inflammasome components and substrates, rendering the system responsive to subsequent activation signals [80]. Structural studies of the inactive NLRP3 cage have shown that LRR-LRR interactions maintain NLRP3 in an autoinhibited conformation. Building on this, NEK7 facilitates the transition of NLRP3 from its inactive cage form into the active inflammasome disc, disrupting these LRR-LRR interactions and enabling the assembly of a functional inflammasome complex necessary for downstream inflammatory signaling [81].

Following priming, NLRP3 activation requires specific stimuli that induce cellular stress or damage [80]. These triggers include potassium ionophores, heme, particulate matter, pathogen-associated RNA, bacterial and fungal toxins, and extracellular ATP, which activates the P2X7 receptor, leading to potassium efflux; crystalline structures such as monosodium urate and silica, which cause lysosomal rupture; and ROS production, which serves as oxidative stress signals [81–83]. These upstream signals converge to promote NLRP3 oligomerization and assembly of the inflammasome complex. Additionally, lysosomal destabilization and the release of cathepsins following phagocytosis of particulate matter further contribute to inflammasome activation [80]. Particularly, these stimuli often reflect cellular disturbances, such as ionic fluxes, mitochondrial dysfunction, or lysosomal damage, which indicate cellular distress.

PTMs of NLRP3 and associated proteins constitute critical regulatory connections in its activation pathway [84]. Phosphorylation, ubiquitination, and SUMOylation can modulate NLRP3’s ability to oligomerize and assemble into the inflammasome complex. For instance, specific phosphorylation events may inhibit NLRP3 activation under resting conditions, while dephosphorylation promotes activation during stress [85]. Similarly, ubiquitination can mark NLRP3 for proteasomal degradation, that functions as a negative regulatory mechanism. These PTMs allow for rapid and reversible modulation of inflammasome activity in response to cellular signals, ensuring a balanced immune response [86].

ROS and Inflammasome Priming

ROS are highly reactive molecules and free radicals derived from oxygen. Although traditionally regarded as harmful metabolic byproducts, ROS are vital signaling molecules that regulate physiological processes such as immune responses and inflammation, notably serving as key mediators in inflammasome priming [87]. Inflammasome priming represents the initial, transcriptional step required for subsequent inflammasome activation. This process typically involves the upregulation of specific inflammasome components, such as NOD, LRR, NLRP3, pro-IL-1β, and pro-IL-18, often driven by PAMPs or DAMPs interacting with PRRs like TLRs [88].

The Role of the Gut-Brain Axis in NLRP3 Activation

The gut-brain axis (GBA) is a complex, bidirectional communication network linking the gastrointestinal tract and the CNS. This axis integrates neural, hormonal, and immune signaling, with the gut microbiota emerging as a critical modulator of these interactions [89]. Recent research has highlighted the role of the NLRP3 inflammasome in mediating central and peripheric inflammatory responses. Intestinal microbiota, a complex community of microorganisms in the gastrointestinal tract, represents a key component in the function of this axis. Microbiotas regulate brain function through the production of active metabolites, such as neurotransmitters and short-chain fatty acids (SCFAs), LPS, lactic acid, bile acids, trimethylamine-N-oxide, and tryptophan derivatives that modulate immune responses and can directly or indirectly activate the NLRP3 inflammasome [90, 91].

Microbial-associated molecular patterns such as LPS interact with TLRs, activating NF-κB and promoting proinflammatory cytokine production (IL-6, TNF-α), which primes NLRP3 activation [91, 92]. SCFAs, particularly propionate, butyrate, and acetate, are produced by gut bacteria fermenting dietary fibers. These metabolites act as histone deacetylase (HDAC) inhibitors, promote regulatory T-cell (Treg) differentiation, and interact with G protein-coupled receptors (GPR41, GPR43) to suppress NF-κB activation, thereby modulating cytokine production and NLRP3 activation [90, 91]. Propionate enhances BBB integrity via free fatty acid receptor 2, reducing the risk of neuroinflammation; this pathway is known as the metabolic pathway [93]. Meanwhile, the immune pathway involves microbial-associated molecular patterns such as LPS recognized by TLRs (especially TLR4), activating NF-κB and leading to the production of proinflammatory cytokines, which are upstream activators of the NLRP3 inflammasome [91, 92]. Elevated circulating LPS, as seen in gut dysbiosis or increased gut permeability, is a potent trigger for systemic and CNS NLRP3 activation [90, 92]. Finally, the neural pathway involves the vagus nerve, and the sympathetic nervous system mediates rapid communication between the gut and brain. Microbial metabolites and inflammatory mediators can influence neural signaling, affecting microglial activation and neuroinflammation [90, 91].

Alterations in microbiota and gastrointestinal dysfunction observed in patients with Parkinson’s disease (PD) and Alzheimer’s disease (AD) indicate a correlation between inflammation observed in the brain and gastrointestinal tract. Differences in gut bacteria composition in neurological pathologies determine patterns of immune cell activation and inflammatory responses [89]. In animal models of PD and AD, an increase in proinflammatory cytokines and NLRP3 components has been observed in brain and gut tissue [94–96]. Interestingly, fecal transplants from animals with post-stroke depression to healthy animals reproduce motor and behavior dysfunction, regarding the role of gut dysbiosis in neuronal dysfunction [97]. Additionally, transplantation of gut microbiota from healthy rats to animals subjected to a PD model induced by manganese reduced brain levels of Aβ, tau, NLRP3, and proinflammatory cytokines [98]. For this reason, targeting gut dysbiosis has become an emerging strategy to attenuate neuroinflammation in degenerative and acquired brain pathologies.

The NLRP3 inflammasome regulates gut microbiota composition, immune responses, and the integrity of the intestinal epithelial barrier, contributing to gut homeostasis [89]. In addition, gut microbiota regulates brain function through regulation of NLRP3 signaling pathways and determines inflammatory response in the periphery, observed in patients with neurodegenerative diseases [1]. Evidence in animal models of neurodegenerative pathologies supports the key role of NLRP3 in enteric and brain inflammation. In an animal model of AD induced by a high-fat diet, treatment for 80 weeks with yeast β-glucan, derived from Saccharomyces cerevisiae, attenuated cognitive dysfunction, activation of microglia, and NLRP3 activation. Yeast β-glucan stimulates the levels of beneficial bacteria and SCFAs, which inhibits NLRP3 activation [99]. Similar results were reported with gingko leaf tea, derived from Gingko biloba, in an MPTP-induced PD mice model. The treatment alleviated motor dysfunction and dopaminergic neuronal loss by increasing the number of SCFA-producing bacteria, which in turn reduces neuroinflammation via the GBA [100]. The production of SCFAs by gut microbiota remodeling regulates the TLR4/MyD88/NLRP3 signaling pathway [101].

In an animal model of PD induced by 6-hydroxydopamina, the probiotic Lactobacillus murinus attenuated motor dysfunction and dopaminergic neuron loss through inhibition of NLRP3 activation. In KO NLRP3 animals, these effects were not observed [102]. Another probiotic that regulates the activation of NLRP3 and neuroinflammation is Komagataella pastoris KM71H, in a mouse model of AD induced by the β1-40 peptide [103]. In a SAMP8 (senescence-accelerated mouse prone 8), a model of AD, oral treatment with Lactiplantibacillus plantarum decreased inflammasome activation in the colon and brain and attenuated cognitive impairment [95]. Similar results were observed with Akkermansia muciniphila in an MPTP-induced PD model that ameliorated neurodegeneration and colonic damage [96]. Thus, experimental evidence highlights the role of NLRP3 activation in the gastrointestinal tract and its influence in neuronal dysfunction through the GBA. Moreover, frequently observed in neurodegenerative diseases, they modulate NLRP3 activation and shape both central and peripheral inflammatory responses, thereby contributing to neuronal degeneration.

Linking Oxidative Stress to NLRP3 Activation

The NLRP3 inflammasome is a key mediator of the inflammatory response, and its activation is intricately linked to cellular oxidative stress (shown in Fig. 2), which is a potent activator of the NLRP3 inflammasome [104]. The connection between oxidative stress and inflammasome activation highlights the critical role of redox homeostasis in immune regulation, as ROS serve as key secondary messengers in NLRP3 activation [105]. Elevated ROS levels serve as both signaling molecules and damaging agents, linking cellular metabolic disturbances to inflammatory responses. This connection is further demonstrated by a critical pathway involving ionic flux, where oxidative stress induces alterations in intracellular ion concentrations [106]. For example, ROS can trigger the opening of specific ion channels, such as the transient receptor potential melastatin-related 2 (TRPM2) channels [107, 108]. The influx of calcium (Ca²⁺) and other cations through TRPM2 which is a potent signal for NLRP3 activation, as it can directly influence the assembly of the inflammasome complex [109].

Fig. 2.

Role of oxidative stress in mediating NLRP3 inflammasome activation within the brain. Illustrates the mechanisms by which oxidative stress influences NLRP3 inflammasome activation in neural tissue. a Elevated reactive oxygen species (ROS) can induce PTMs, such as S-glutathionylation, on NLRP3 cysteine residues, promoting conformational changes that facilitate activation. b Mitochondrial damage caused by oxidative stress results in the release of mitochondrial DNA (mtDNA) and cardiolipin into the cytoplasm, acting as damage-associated molecular patterns (DAMPs) that directly stimulate NLRP3. c ROS-mediated activation of ion channels like TRPM2 leads to calcium influx, further promoting inflammasome assembly. d During oxidative stress, thioredoxin-interacting protein (TXNIP) dissociates from thioredoxin (TRX) and binds to the leucine-rich repeat (LRR) domain of NLRP3, serving as a critical activator. These pathways contribute to neuroinflammatory processes driven by oxidative stress. Created in BioRender. Torres, A. (2026) https://BioRender.com/xujyzk2.

The oxidative environment created by ROS may also modify key cysteine residues on NLRP3 or other inflammasome components, promoting activation in response to cellular stress signals. This modification, often in the form of S-glutathionylation or other PTMs, can alter the protein’s conformation and function, thereby priming it for activation [110]. The NLRP3 protein contains several cysteine residues that are highly susceptible to oxidation and are essential for maintaining an autoinhibited conformation [111, 112]. Under basal conditions, these cysteine residues are in a reduced state, and the NLRP3 protein is maintained in an inactive, closed conformation [112]. However, when the cell is subjected to oxidative stress, the increased levels of ROS can lead to the oxidation of these cysteine residues. This process can be mediated by the depletion of reduced GSH, leading to a shift in the redox potential of the cell towards a more oxidized state [113]. The oxidized cysteine residues can then form disulfide bonds or become S-glutathionylation, a process where a GSH molecule is covalently attached to the cysteine residue [114]. These modifications induce a conformational change in NLRP3, moving it from its inactive, autoinhibited state to an active, oligomerized state [100, 115]. This conformational change is essential for the recruitment of the adapter protein, ASC, and subsequent formation of the inflammasome complex [85].

The molecular pathway involving NLRP3 cysteine modification is tightly regulated by the cellular redox environment. A key regulator in this pathway is TRX, a small redox protein that plays a significant role in maintaining the redox homeostasis of the cell [116]. TRX and its reductase (TRXR) are responsible for reducing disulfide bonds and protecting cysteine residues from oxidation. Under normal conditions, TRX maintains NLRP3 in a reduced, inactive state by preventing the formation of intermolecular disulfide bonds. However, during oxidative stress, TRX itself can become oxidized and inactivated [117]. This inactivation of TRX disrupts its ability to maintain the reduced state of NLRP3, leaving it vulnerable to redox modifications. The inactivation of TRX can also be caused by direct modification of its active site cysteines by ROS [118]. The inactivation of TRX leads to an increase in oxidized NLRP3, which is then free to undergo the conformational changes necessary for inflammasome assembly [119]. This creates a feed-forward loop where oxidative stress not only directly modifies NLRP3 but also disables the antioxidant systems, further promoting inflammasome activation [120, 121].

The assembly of the NLRP3 inflammasome complex, which includes NLRP3, ASC, and pro-caspase-1, leads to the formation of a large oligomeric structure known as the ASC speck [62]. This speck serves as a platform for the auto-cleavage of pro-caspase-1 into its active form that in turn cleaves the proinflammatory cytokines pro-IL-1β and pro-IL-18 [122]. These cytokines are major drivers of inflammatory response and are implicated in various neuroinflammatory disorders. Furthermore, caspase-1 activation also leads to the cleavage of GSDMD, a pore-forming protein. As mentioned, the N-terminal fragment of GSDMD translocates to the cell membrane, forming pores that lead to cell swelling and eventual pyroptotic cell death [123]. The entire process, from ROS generation to NLRP3 cysteine modification and subsequent caspase-1 activation, forms a critical molecular pathway connecting oxidative stress to neuroinflammation [124].

Finally, oxidative stress can cause mitochondrial dysfunction and damage, leading to the release of mitochondrial components into the cytosol. These include oxidized mitochondrial DNA (mtDNA) and cardiolipin, which can function as DAMPs that directly bind to NLRP3, triggering its activation [125]. This intricate interplay between ROS, mitochondrial integrity, and downstream signaling cascades underscores the central role of oxidative stress as an integration point for a wide range of NLRP3-activating stimuli [126].

Mitochondrial and Lysosomal Dysfunction and NLRP3 Activation

Mitochondria are one of the primary sources of ROS within cells, especially during stress conditions such as infection, metabolic overload, or hypoxia. Mitochondrial ROS (mtROS) generation has been strongly linked to NLRP3 activation, with studies demonstrating that mitochondrial damage leads to increased mtROS levels that serve as danger signals [127]. Additionally, the release of mitochondrial DNA into the cytoplasm, coupled with elevated mtROS, acts as a potent stimulus for inflammasome assembly. These mitochondrial signals integrate metabolic stress with immune responses, emphasizing the role of mitochondrial integrity in controlling inflammation [128].

Upon encountering activating stimuli like PAMPs or DAMPs, mitochondrial metabolism is altered, leading to an increase in mtROS production [129]. First, mtROS can directly oxidize and inactivate the antioxidant protein TRX. This inactivation causes the dissociation of TRX from its inhibitor, TRX-interacting protein (TXNIP) [130]. Dissociated TXNIP then directly binds to the LRR domain of NLRP3, leading to its conformational change and subsequent oligomerization. Also, TXNIP translocates to the mitochondria, where it binds to TRX2, leading to mitochondrial dysfunction [131].

Oxidative stress can also lead to lysosomal membrane permeabilization and damage [132]. This results in the leakage of lysosomal enzymes, such as cathepsin B, into the cytoplasm. Cathepsin B, in turn, can activate NLRP3, either directly or indirectly, contributing to inflammasome assembly and the subsequent inflammatory cascade [133, 134]. The accumulation of protein aggregates and other cellular debris in neurodegenerative diseases often exacerbates lysosomal dysfunction, creating prolific ground for NLRP3 activation [135].

ROS contributes to inflammasome priming through several mechanisms. Firstly, low to moderate levels of ROS, generated by NOX or mitochondrial respiration, can activate redox-sensitive transcription factors, notably NF-κB [136]. NF-κB activation is a critical event in priming, leading to the transcriptional upregulation of genes encoding inflammasome components (NLRP3 gene) and proinflammatory cytokines. This ensures that the cell has sufficient building blocks for rapid inflammasome assembly upon a secondary activation stimulus [137]. Secondly, ROS can directly modify cellular proteins and lipids, alter their function, and contribute to the intracellular environment conducive to priming [138]. For instance, oxidative stress can lead to the dissociation of TXNIP, which then binds to and facilitates NLRP3 inflammasome activation [119]. Furthermore, mitochondrial ROS, specifically, have been implicated in driving the initial steps of NLRP3 priming by inducing mitochondrial dysfunction and subsequent release of mitochondrial DNA or other DAMPs into the cytoplasm [139].

ROS are not merely detrimental byproducts but active participants in the intricate cascade leading to inflammasome assembly. Their capacity to modulate crucial signaling pathways, particularly NF-κB, and to induce cellular changes that expose or upregulate inflammasome components underscores their indispensable role in inflammasome priming, thus inducing inflammatory responses in the CNS [140].

Implications for Neuroinflammatory Diseases

The interplay between the NLRP3 inflammasome and oxidative stress is a critical factor in the pathogenesis of several neuroinflammatory diseases [59] (shown in Fig. 3). Oxidative stress, a state of imbalance between the production of ROS and the cells’ antioxidant defenses, acts as a potent trigger for NLRP3 activation in the brain, particularly in microglia and astrocytes [141]. This leads to a vicious cycle of inflammation and cellular damage that is a hallmark of many neurodegenerative disorders.

Fig. 3.

Modulation of inflammation in acquired and degenerative brain pathologies through NLRP3 inflammasome activation induced by oxidative stress. Demonstrates the pathological mechanisms linking oxidative stress to NLRP3 inflammasome activation in brain pathologies. In neurodegenerative diseases, the accumulation of misfolded proteins such as tau, α-synuclein, and Aβ plaques leads to mitochondrial dysfunction, excitotoxicity, and elevated reactive oxygen species (ROS) production. In contrast, acquired brain injuries including ischemia, hematoma expansion, and mechanical trauma directly induce mitochondrial impairment, excitotoxicity, and oxidative stress. Created in BioRender. Torres, A. (2026) https://BioRender.com/vcc3s1p.

Alzheimer’s Disease

AD is characterized by the presence of extracellular amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), which are often found in close association with activated microglia [142]. Autopsy studies have confirmed that these pathological features are surrounded by microglial cells, suggesting an immune response [143]. Recent research further indicates that the accumulation of pathogenic Aβ and tau proteins may lead to microglial dystrophy, a deterioration of these immune cells, which can, in turn, accelerate neuronal loss and promote the ongoing deposition of NFTs and Aβ, both in in vitro and in vivo models [144].

Oxidative stress plays a pivotal role in the pathogenesis of AD by acting as a critical activator of the NLRP3 inflammasome, a key driver of chronic neuroinflammation [145]. In the context of AD, a vicious cycle is established where Aβ plaques, hyperphosphorylated tau aggregates, and the formation of intraneuronal NFTs of tau protein induces oxidative stress, which in turn triggers the activation of the NLRP3 inflammasome [146]. This activation then amplifies the neuroinflammatory response, leading to further neuronal damage and disease progression [147]. The intricate interplay between these pathways highlights the NLRP3 inflammasome as a central mediator of neuroinflammation in AD and a promising therapeutic target.

In brain regions affected by AD, microglial cells are frequently localized near amyloid-β (Aβ) plaques, where they participate in plaque clearance through phagocytic uptake and proteolytic degradation mechanisms [148]. NLRP3 inflammasome activation occurs in response to various Aβ species, including fibrils, oligomers, and protofibrils. Aβ triggers microglial activation via multiple pathways, notably NF-κB, which upregulates NLRP3 and proinflammatory cytokines such as pro-IL-1β [149, 150]. Soluble Aβ destabilizes lysosomes, leading to increased production of mtROS and cathepsin release and NLRP3 inflammasome activation [145]. This mtROS acts as a potent activating signal for the NLRP3 inflammasome. Concurrently, Aβ oligomers disrupt mitochondrial function, causing oxidative stress and mtDNA release into the cytosol due to mitochondrial damage, which can also serve as DAMP, further contributing to NLRP3 activation [151]. Progressive NLRP3 activation in AD results in sustained microglial activation, impairing Aβ clearance and promoting its buildup [152]. Evidence from APP/PS1 transgenic mice deficient in NLRP3 shows decreased Aβ deposition, indicating that NLRP3 plays a role in Aβ accumulation and disease advancement [153].

On the other hand, recent studies have demonstrated that tau proteins activate the NLRP3 inflammasome in microglia through an ASC-dependent pathway, promoting IL-1β secretion and neuroinflammation, while also influencing tau phosphorylation processes that contribute to hyperphosphorylation and aggregation in neurons [154]. Moreover, the presence of hyperphosphorylated tau aggregates, a hallmark of AD pathology, directly contributes to NLRP3 inflammasome activation. These aggregates, often in the form of NFTs, are recognized by microglial TLRs, initiating a signaling cascade that includes the NF-κB pathway. This pathway promotes the transcriptional upregulation of NLRP3 and its associated proinflammatory cytokines, specifically pro-IL-1β and pro-interleukin-18 (pro-IL-18). The activation of the NLRP3 inflammasome subsequently leads to the proteolytic cleavage and secretion of mature IL-1β and IL-18, cytokines that intensify neuroinflammation and accelerate disease progression [155]. Further, the process of tau uptake by microglial lysosomes can be a potent trigger for inflammasome activation. This uptake can lead to lysosomal rupture and the release of proteases like cathepsin B into the cytoplasm, which can directly activate the NLRP3 inflammasome [154]. The role of tau in this pathway extends beyond the aggregates, as even precursor tau species have been shown to induce neuroinflammation and cognitive deficits through NLRP3-dependent mechanisms [156]. Consequently, the NLRP3 inflammasome presents a compelling therapeutic target for modulating the neuroinflammatory cascade and potentially slowing the progression of AD.

Parkinson’s Disease

Oxidative stress is a central driver in the pathogenesis of PD, where it acts as a potent activator of the NLRP3 inflammasome [157]. In PD, a harmful cycle emerges where the aggregation of α-synuclein (α-syn) and mitochondrial dysfunction induce oxidative stress, which then triggers the activation of the NLRP3 inflammasome in microglia and other CNS cells [158]. This activation amplifies the inflammatory response, leading to the progressive degeneration of dopaminergic neurons in the substantia nigra, which are particularly vulnerable to oxidative damage [159, 160]. This intricate interplay underscores the NLRP3 inflammasome as a crucial link between oxidative stress and neurodegeneration in PD.

The activation of the NLRP3 inflammasome in PD is a multi-step process. The initial “priming” signal often comes from the presence of misfolded and aggregated α-synuclein (α-syn), a characteristic feature of PD, which interacts synergistically with PARthanatos [161]. Oligomeric α-syn can bind to DNA, inhibit topoisomerases, and promote DNA supercoiling alongside double-strand breaks, leading to the activation of PARP-1 [162]. Additionally, α-syn aggregates can disrupt mitochondrial membranes, causing a loss of membrane potential and the release of apoptosis-inducing factors (AIF). Research indicates increased PARP-1 activity in neurons overexpressing the A53T mutant form of α-syn, whereas mice lacking α-syn are resistant to MPTP-induced PARthanatos [163, 164]. PARthanatos interacts intricately with both apoptosis and necroptosis. Initially, activation of PARP-1 can temporarily inhibit apoptosis by suppressing caspase-3 activity; however, sustained NAD+ depletion eventually drives cells toward AIF-mediated cell death [165, 166]. Conversely, apoptotic mediators such as caspase-3 can cleave PARP-1 into fragments that promote cell death, thereby enhancing PAR signaling [167]. During PARthanatos, released PAR polymers function as DAMPs, triggering microglial activation and pyroptosis in nearby neurons [105]. Animal studies have demonstrated that knock out (KO) of NLRP3 or treating with its inhibitor, MCC950, significantly decreases neuronal pyroptosis and improves motor function in mice overexpressing α-syn, highlighting the key role of the α-syn-NLRP3 pathway in PD [168].

Misfolded, aggregated, or fibrillar α-syn can also trigger pyroptosis through multiple mechanisms. For example, lysosomal dysfunction arises when α-syn aggregates are phagocytosed by microglia or neurons but resistant to lysosomal degradation [169]. This resistance leads to lysosomal membrane permeabilization (LMP), resulting in the release of cathepsin B into the cytoplasm, which directly activates the NLRP3 inflammasome [170]. Additionally, interaction of α-syn with mitochondrial membranes triggers bursts of ROS, especially hydroxyl radicals (OH) [171]. This impairs Complex I activity and causes increased production of superoxide anion (O-2) and hydrogen peroxide (H₂O₂) [172]. These ROS can oxidize mitochondrial DNA or directly stimulate NLRP3 activation. Furthermore, extracellular α-syn acts as a DAMP, binding to TLR2 and TLR4 on microglia, initiating an intracellular signaling cascade via the NF-κB pathway [173]. This leads to the transcriptional upregulation of NLRP3, pro-IL-1β, and pro-IL-18, preparing the cell for the inflammasome’s full activation. The subsequent release of IL-1β and IL-18 into the extracellular space promotes a state of chronic neuroinflammation, attracting and activating more immune cells, and ultimately leading to the degeneration of dopaminergic neurons [174].

As mentioned above, a crucial mediator of pyroptosis is gasdermin D (GSDMD), which forms plasma membrane pores via the N-terminal domain, initiating cell death and releasing proinflammatory factors (IL-1β, IL-18, HMGB1), which recruits peripheral immune cells and activates neighbor glial cells, amplifying the neuroinflammatory feedback loop [174]. In PD, this process has different effects, for example: GSDMD pores disrupt endoplasmic reticulum and mitochondria membranes in dopaminergic neurons, which induces calcium overload and energy depletion, inducing autonomous neuronal death. Also, IL-1β activates astrocytes and microglia, which produces TNF-α, NO, and O-2, activating NLRP3 in adjacent neurons [175]. In PD postmortem patients, analyses of the substantia nigra, the brain region most affected by PD, show that the presence of the active pyroptotic protein GSDMD-N (N-terminal domain) aligns with regions of extensive neuronal death. Furthermore, the severity of motor symptoms in patients with PD has been found to correlate with increased levels of the proinflammatory cytokine interleukin-1β (IL-1β) in the cerebrospinal fluid, highlighting IL-1β as a potential biomarker for disease progression [176]. Emerging evidence indicates that activation of the NLRP3 inflammasome in microglia may enhance exosome release and contribute to the propagation of α-synuclein, thereby playing a role in PD pathogenesis [177].

Multiple Sclerosis

Recent research highlights the significant involvement of the NLRP3 inflammasome and oxidative stress in the underlying mechanisms of multiple sclerosis (MS). The NLRP3 inflammasome is activated by danger signals like myelin debris and cellular stress in MS [178]. Certain NLRP3 gene variants, including rs-10754558, rs-35829419, rs-3806265, and rs-4612666, are associated with increased MS risk, while others, like Q705K, correlate with greater disease severity, suggesting a role in disease progression [179, 180]. In the experimental autoimmune encephalomyelitis (EAE) model, elevated NLRP3 expression has been observed, and NLRP3 knockout mice show reduced immune cell infiltration and milder symptoms [181]. Cytokines generated through NLRP3 activation have been implicated in processes of demyelination and neurodegeneration [182]. In MS, IL-1β and IL-18 are involved early in disease progression, with IL-1β facilitating BBB disruption [183, 184]. Activated astrocytes and endothelial cells release cytokines that weaken junctions, enabling immune cell infiltration. Elevated NLRP3 and IL-1β gene expression in MS lesions and increased serum levels of ASC, caspase-1, and IL-18 suggest inflammasome activation plays a significant role in MS pathology [185].

In addition, activated astrocytes secrete chemokines that recruit leukocytes into the CNS, contributing to MS pathogenesis [186]. Proinflammatory cytokines and chemokines activate microglia, which function as antigen-presenting cells that stimulate infiltrating CD4+ T cells, amplifying neuroinflammation. These T cells, in turn, secrete cytokines that further activate microglia, creating a feedback loop that sustains neuroimmune responses [187]. Microglia, astrocytes, and CD4+ T cells are key contributors to NLRP3 inflammasome activation in MS; increased NLRP3 and IL-1β expression in microglia correlates with demyelination, underscoring their central role [188]. Activated microglial NLRP3 promotes astrocyte transformation into the neurotoxic A1 phenotype, thereby exacerbating cognitive impairments [187]. Evidence suggests that brain infiltration of T cells driven by NLRP3 activation is more critical for disease progression than changes in T cell populations alone [189]. The NLRP3 inflammasome links innate and adaptive immunity by inducing IL-1β and IL-18 secretion, facilitating immune cell infiltration and modulating T and B cell activity. NLRP3 activation in T cells promotes proinflammatory cytokine production, contributing to MS progression [190]. Additionally, B cell activity is connected to NLRP3, with the B cell-activating factor (BAFF) activating the inflammasome via cIAP-TRAF2 interactions, potassium efflux, and ROS production dependent on Src kinase [191].

Elevated ROS levels are observed in MS lesions, where oxidative stress damages oligodendrocytes and neurons, accelerating disease progression [192]. Microglia and infiltrating macrophages produce proinflammatory mediators and radicals such as superoxide, hydroxyl radicals, hydrogen peroxide, and RNS like nitric oxide, contributing to tissue injury and inflammation [193]. Activation of immature myeloid cells like myeloid-derived suppressor cells (MDSCs) also increases ROS and nitric oxide production [194]. In MS lesions, enzymes like MPO generate hypochlorous acid, and oxidized lipids and DNA accumulate in myelin, oligodendrocytes, and neurons, indicating oxidative damage linked to microglial and macrophage activation, characterized by NOX expression (p22phox) [192, 195].

Animal models, such as EAE, replicate these oxidative processes, showing elevated ROS in microglia and macrophages [196]. Therapeutic strategies such as CAT and heme oxygenase-1 (HO-1) reduce oxidative injury and disease severity, while mitochondrial stabilization decreases axonal damage [197, 198]. Oxidative stress directly harms neural tissue and activates the NLRP3 inflammasome, promoting inflammation and tissue destruction. Activation of the Nrf2 pathway enhances antioxidant defenses, reducing ROS, microglial activation, and myelin degradation, thereby offering neuroprotection [199]. The interplay between oxidative stress and NLRP3 activation is critical in initiating and sustaining neuroinflammation in MS [198].

Other Neurodegenerative Disorders

It has been demonstrated that post-mortem brain tissue from patients with amyotrophic lateral sclerosis (ALS) exhibits elevated levels of NLRP3, ASC, caspase-1, and IL-1β [200, 201]. Moreover, a particularly interesting observation has shown that repetitive TBI, a process closely linked to neuroinflammation, accelerates the onset and progression of familial ALS in mice [202]. In this study, it was also found that targeting the Sarm1 pathway, which mediates nerve fiber degeneration, may represent a viable therapeutic strategy for injury-accelerated ALS, highlighting the importance of targeting a specific inflammatory and degenerative pathway in this context [202].

Finally, while the research does not explicitly connect NLRP3 to Huntington’s disease (HD) or epilepsy, it emphasizes that oxidative stress, mitochondrial dysfunction, and neuroinflammation are common pathological features. Since these factors are canonical activators of NLRP3, its involvement in these conditions is strongly implied [203].

Ischemic Stroke

Ischemic injury is the most common type of stroke. The obstruction of blood supply to a specific brain region leads to an inadequate supply of glucose and oxygen to the brain tissue. In some cases, the restoration of blood supply (reperfusion) determines the ischemic/reperfusion (I/R) injury, characterized by oxidative stress, inflammation, and neuronal death. While many processes occur simultaneously after I/R, oxidative stress is the major mechanism that affects and exacerbates the other molecular events, leading the neuron to death [204]. One of these events is the inflammation regulated by the NLRP3 inflammasome, a crucial component in the pathogenesis of ischemic stroke [205]. Inhibition of the NLRP3 inflammasome in rats with ischemic injury limited inflammation, improving neurological dysfunction and neurogenesis [206]. In addition, a reduction in infarction area and edema has been reported in mice with I/R injury treated with MCC950, the NLRP3 inhibitor [207]. However, diverse studies suggest that modulation of oxidative stress down-regulates inflammasome activation.

In NADPH-oxidase 2 (NOX2) KO mice subjected to cerebral ischemia, the levels of NLRP3 and neuronal damage were reduced compared to wild-type animals, suggesting that ROS produced by NOX2 participates in NLRP3 activation [208]. In the same way, edavaravone dexborneol (EDB), a synthetic molecule with ROS scavenger activity, reduced inflammatory cytokine and NLRP3 component levels, modulating microglia pyroptosis [209]. Similar results were reported in the same animal model with curcumin, a natural antioxidant agent. This condition reduces GSDMD-N, caspase-1, NLRP3, IL-1β, and IL-18 protein levels, as well as the proportion of Iba-1 positive cells, thereby improving sensorimotor function [210]. Another molecule with antioxidant properties that decreased inflammasome activation and neuronal damage in an experimental ischemic stroke is methyl isoeugenol [211]. These results suggest that neuroprotective effects observed with antioxidants in experimental models of ischemic stroke can be mediated by regulation of the inflammasome NLRP3 activation and the inflammatory response.

Hemorrhagic Stroke

This type of stroke represents a devastating disease, with high mortality and neurological dysfunction. The rupture of blood vessels in the brain leads to a primary mechanical injury characterized by hematoma expansion and increases in intracranial pressure. Besides, a secondary injury is mediated by oxidative stress and inflammation [212]. The activation of inflammasome NLRP3 plays a pivotal role in the inflammation after intracerebral hemorrhage (ICH), aggravating brain edema and neurological dysfunction [213]. In the same way, oxidative stress is associated with neuronal death after ICH and mediates several molecular events in the neurons, such as apoptosis, necrosis, necroptosis, and BBB disruption [214]. Also, in a model of ICH in rats, the synthetic antioxidant Edaravone reduced NLRP3 expression in microglia and the protein levels of IL-1β and caspase-1, alleviating brain edema and neurological deficit [215]. Similar results were reported with silymarin, a flavonoid with antioxidant properties [216]. Additionally, resveratrol, a polyphenol with antioxidant properties, reduced microglial activation and NLRP3 expression after subarachnoid hemorrhage (SAH) in an animal model and attenuated brain edema and neurological impairment [217].

Traumatic Brain Injury

TBI occurs at high rates among older adults and children, and the survivors are at risk for long-term cognitive, emotional, and behavioral impairments [218]. Cerebrospinal fluid NLRP3 levels increase after moderate and severe TBI in children and adults [219, 220]. Furthermore, in mice subjected to experimental mild TBI, the inhibition of NLRP3 using MCC950 prevents the up-regulation of IL-1β and caspase-1 levels and reduces cerebral edema and neurological impairment [221]. It is suggested that oxidative stress mediates NLRP3 activation during TBI. In NOX2 KO mice subjected to controlled cortical impact, both protein and mRNA levels of ASC, pro-IL-1β, and caspase-1 were attenuated compared with wild-type animals. In the same way, the lesion size was smaller in NOX2 KO animals. Additionally, authors reported a reduction of the TXNIP-NLRP3 interaction in NOX2 KO mice, suggesting a mechanism associated with this oxidative stress sensor [222].

Synthetic antioxidants such as edaravone and natural compounds such as resveratrol mediate protection in animal models of TBI [223, 224]. Catalpol, a natural antioxidant, primarily found in the roots of plants like Rehmannia glutinosa, attenuates the observed increase of NLRP3, ASC, IL-1β, and caspase-1, as well as Iba-1 levels. These effects were confirmed with a reduction in brain edema, BBB rupture, and neurological deficit [225]. Similar results were reported with the use of oridonin, a natural ent-kaurane diterpenoid isolated from Rabdosia rubescens, which inhibited the expression of the components of NLRP3 through stimulation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway [226]. As mentioned above, oxidative stress regulates the NLRP3 activation and the inflammation in acquired brain pathologies.

Therapeutic Perspectives

Considering the role of oxidative stress in NLRP3 inflammasome regulation, targeting ROS production is a promising therapeutic approach for inflammatory and neurological diseases (shown in Fig. 4) [227]. Antioxidants that scavenge ROS or agents that improve mitochondrial function can potentially attenuate inflammasome activation and reduce excessive inflammation. Clinical trials exploring such interventions are underway, aiming to restore redox balance and mitigate inflammation-driven pathology [228]. Ultimately, understanding the precise molecular mechanisms connecting oxidative stress to NLRP3 activation may facilitate the development of targeted therapies for conditions characterized by chronic inflammation [229]. Although some antioxidant therapies have limited clinical success, ongoing research seeks more effective and targeted interventions to restore redox balance and protect neuronal integrity. For example, N-acetyl-L-cysteine (NAC) is a recognized antioxidant that serves as a precursor to GSH, exerting its protective effects by scavenging free radicals and inhibiting ROS. In ethanol exposure models, NAC helps improve cognitive function, decrease Aβ buildup, and reduce inflammation. It also restores levels of key neurodevelopmental proteins, suggesting its potential to mitigate alcohol-related neurodegeneration and possibly slow AD progression [230].

Fig. 4.

Therapeutic strategies targeting NLRP3 inflammasome via oxidative stress modulation. Illustrates therapeutic agents targeting NLRP3 inflammasome activation, emphasizing modulation of oxidative stress. a N-acetylcysteine (NAC), a precursor to glutathione, and edaravone, a synthetic ROS scavenger, directly neutralize ROS. b Natural compounds such as celastrol activate Nrf2 signaling, upregulating antioxidant gene expression to restore redox homeostasis. c Salidroside from Rhodiola rosea inhibits TLR4/NF-κB pathways, reducing NLRP3 activation. d Pharmacological inhibitors like OLT1177 (dapansutrile) bind to the NATCH domain of NLRP3, impairing ATPase activity and oligomerization. e MCC950 and ZYIL1 target the NACHT domain, inhibiting ATPase function and conformational changes necessary for inflammasome assembly. f Lonidamine (LND) interferes with ASC oligomerization by binding to its CARD domain, thereby preventing inflammasome formation. These strategies highlight the potential for targeted modulation of NLRP3 in neuroinflammatory conditions. Created in BioRender. Torres, A. (2026). https://BioRender.com/ujfc8qp.

Additionally, interventions aimed at improving mitochondrial function and reducing inflammation are under investigation. While some antioxidant therapies have shown limited clinical efficacy, ongoing research continues to explore more targeted and effective means to mitigate oxidative damage and preserve neuronal integrity in CNS disorders [231]. The molecular link between oxidative stress and NLRP3 activation may facilitate the development of therapies for chronic inflammatory conditions. Therapeutic strategies focus on disrupting this axis by targeting specific components to mitigate persistent inflammation and tissue damage.

NLRP3 Inflammasome Inhibitors

The development of small-molecule compounds that directly inhibit the NLRP3 inflammasome represents a major area of therapeutic research (shown in Fig. 4). MCC950 (also known as CP-456773) is a prime example, a potent and selective NLRP3 inflammasome inhibitor that has been extensively evaluated in preclinical models for its ability to block both canonical and non-canonical NLRP3 activation. Its mechanism of action involves inhibiting ATP hydrolysis by specifically interacting with the Walker B motif within the NLRP3 NACHT domain [232]. Preclinical studies have shown that MCC950 treatment in aged AD mouse model improved cognition, reduced Aβ pathology, and lowered IL-1β levels [233]. Similarly, in PD models, it effectively reduced α-synuclein aggregation, neurodegeneration, and motor deficits. In cerebral ischemia-reperfusion injury and intracerebral hemorrhage, the NLRP3 inflammasome is a key causative factor [168, 234]. Pharmacological inhibition with MCC950 has been shown to attenuate cerebral infarction and edema, while repurposed diabetes drugs like Glibenclamide and Pioglitazone provide neuroprotective effects by inhibiting NLRP3 activation in these contexts [207, 235, 236].

Other direct NLRP3 inhibitors include OLT1177 (dapansutrile), ZYIL1, and fenamate NSAIDs such as mefenamic acid, which have been reported to be stronger NLRP3 inhibitors than other non-steroidal anti-inflammatory drugs and have shown efficacy in improving cognition in AD models by reducing IL-1β [237, 238]. Additional compounds such as JC-124, JC-171, and lonidamine (LND) are also under investigation. LND, for instance, directly binds to the ASC adaptor protein to inhibit its oligomerization and prevent inflammasome assembly.

Targeting Upstream Pathways: Modulating Oxidative Stress and Transcription

Instead of directly inhibiting the inflammasome, an alternative strategy involves modulating upstream pathways that regulate its activation. The Nrf2-NLRP3-caspase-1 axis is a particularly promising target [239]. Celastrol, a potent Nrf2 activator, has demonstrated neuroprotective effects in PD models. Its mechanism involves activating the Nrf2 pathway, a key transcription factor that induces antioxidant and anti-inflammatory enzymes. This Nrf2 activation, in turn, suppresses the NLRP3 inflammasome activation, leading to the inhibition of caspase-1 and reduced neuroinflammation, which protects against the loss of dopaminergic neurons and mitigates motor deficits [239]. Another example is β-hydroxybutyrate, which inhibits the NLRP3 inflammasome by preventing potassium (K+) efflux, suppressing NLRP3/ASC oligomerization and speck formation [240]. In multiple sclerosis, a key therapeutic mechanism involves inhibiting the activity of SP1 in lymphocytes, leading to their retention within lymph nodes and consequently decreasing their infiltration into the brain.

Fingolimod, a prodrug that is converted into its active form, fingolimod-P, exerts its effects by binding to various sphingosine-1-phosphate (S1P) receptors (including S1P1, S1P3, S1P4, and S1P5), thereby modulating the S1P signaling pathway to achieve this immunomodulatory action [241]. Another example is canakinumab, an anti-IL-1β monoclonal antibody, which is under investigation in a phase II trial to assess its impact on cognition in patients with mild cognitive impairment or early AD. Elevated IL-1β levels and genetic variations are linked to AD progression. In the brain, activation of the NLRP3 inflammasome promotes IL-1β production, increasing neuroinflammation [242]. Although agents like canakinumab and anakinra show promise, evidenced by animal studies indicating reduced inflammation and cognitive deficits, limitations such as limited drug penetration into the brain, safety concerns, and the complex inflammatory pathways downstream of NLRP3 activation may restrict their effectiveness in AD treatment. The trial evaluates cognitive, safety, and neuroinflammatory outcomes over 20 weeks, with findings expected by February 2026 [243].

Phytochemicals and Natural Compounds

A growing body of evidence suggests that phytochemicals derived from plants may represent a new frontier in the therapeutic management of neuroinflammatory diseases by targeting the NLRP3 inflammasome. These compounds, which include polyphenols, flavonoids, and triterpenoids, exhibit anti-inflammatory and neuroprotective properties through multiple mechanisms [244, 245]. Some work by inhibiting upstream NLRP3 activation through the suppression of ROS generation, while others directly block NF-κB-mediated transcription or NLRP3 oligomerization. Salidroside, a phenolic glycoside and the main active ingredient of Rhodiola Rosea, provides a compelling example. It has been shown to ameliorate AD pathology symptoms by inhibiting the TLR4/NF-κB/NLRP3/caspase-1 signaling pathway, thereby reducing pyroptosis and Aβ accumulation [246]. Similarly, in ischemic stroke, salidroside utilizes the TLR4/NF-ƘB pathway to inhibit NLRP3 inflammasome activation in microglia [247].

Also, emodin, a compound extracted from herbs like rhubarb, can improve symptoms in EAE, an animal model of MS. Its mechanism involves regulating the SIRT1/PGC-1α/NLRP3 signaling pathway to inhibit microglial inflammation [248]. Other antioxidants, like rutin, have also been shown to ameliorate inflammation and oxidative stress by suppressing the NLRP3 inflammasome signaling pathway through regulating the expression of proinflammatory factors such as IL-1β, COX2, inducible nitric oxide synthase, and TNF-α and by acting on signaling pathways such as TLR4/NF-ƘB and the NLRP3 inflammasome [249]. Compounds such as NAC have shown the ability to protect cells from oxidative stress and inhibit disease severity in animal models of MS [250]. Also, MitoTEMPO, MitoQ, MitoVitE, SKQ1 that are mitochondria-targeted antioxidants designed to accumulate within the mitochondria to scavenge mitROS have been shown to reduce oxidative damage in several neurological disorders such as PD, AD, HD, ALS, and MS [251]. Bixin, a compound that scavenges ROS, has also been shown to inhibit disease severity in a preclinical model of MS [252]. By reducing the overall oxidative burden, these agents can break the cycle at its source, preventing NLRP3 activation and the subsequent inflammatory cascade.

Other promising strategies include natural compounds such as sinomenine and autophagy regulators like liraglutide, which have shown efficacy in EAE models by modulating NLRP3 inflammasome activity [253]. Phytochemicals like resveratrol have shown neuroprotective effects in epilepsy models by reducing oxidative stress and neuroinflammation, which suggests an indirect, but potentially significant, modulation of the NLRP3 axis [254].

The existence of a self-perpetuating, multi-layered pathogenic cycle suggests that single-agent therapies may be insufficient to fully halt disease progression. An expert analysis of this axis points towards the need for a paradigm shift toward dual-targeting or multi-modal therapeutic strategies. A combined approach that simultaneously inhibits NLRP3 activation and reduces oxidative stress has the potential to provide more robust neuroprotection by disrupting the vicious cycle at multiple points [255]. Table 1 summarizes key therapeutic compounds targeting this axis, providing an overview of their mechanism and status based on preclinical and clinical research.

Table 1.

Key therapeutic agents targeting the NLRP3-oxidative stress axis

Compound name	Primary target	Mechanism of action	Disease model(s) tested	Clinical status/key findings	References
MCC950	NLRP3 inflammasome	Inhibits ATP hydrolysis, blocking oligomerization and activation	AD, PD, ICH, MS (EAE)	Preclinical. Clinical studies in other diseases temporarily discontinued due to liver toxicity	[121, 206, 221, 233]
OLT1177 (dapansutrile)	NLRP3 inflammasome	Directly inhibits NLRP3 inflammasome	MS	Demonstrated safety in humans and efficacy in animal models of MS; in early clinical studies	[237]
Vent-02	NLRP3 inflammasome	Small-molecule inhibitor of NLRP3	MS	Promising preclinical data; in clinical settings	[256]
Celastrol	Nrf2	Activates Nrf2 pathway, which suppresses NLRP3 inflammasome	PD	Preclinical. Promising disease-modifying agent in models	[239]
β-Hydroxybutyrate	NLRP3 inflammasome	Attenuates K+ efflux, suppressing NLRP3/ASC oligomerization	Stroke, AD, PD	Experimental efficacy shown in models; clinical use may be limited by side effects	[240]
Salidroside	TLR4/NF-κB/NLRP3 pathway	Inhibits upstream signaling, reducing pyroptosis and Aβ accumulation	AD	Preclinical. Phytochemical with multi-target effects	[246, 247]
Fingolimod	S1P receptor, NLRP3 inflammasome	Modulates S1P signaling; reduces inflammasome activity in responders	MS	FDA-approved drug for MS. Its effect on ASC oligomerization is a potential biomarker	[241]
Glibenclamide	NLRP3 inflammasome	Inhibits NLRP3 activation in microvascular endothelial cells	ICH	Repurposed diabetes drug with neuroprotective effects	[235]
Fenamate NSAIDs	NLRP3 inflammasome, COX enzymes	Stronger NLRP3 inhibition than other NSAIDs; reduces IL-1β release	AD	Preclinical. Also has off-target effects on COX enzymes	[238]
Edaravone	Free radical scavenger, NLRP3	Scavenges free radicals; also regulates NLRP3 inflammasome activation	PD, ALS	Phase III trial for ALS. Approved for ALS in some countries	[209, 215, 223, 257]
Rutin	NLRP3 inflammasome	Suppresses NLRP3 inflammasome signaling pathway to reduce OS	Ulcerative colitis (UC), LPS-induced cells	Preclinical. Phytochemical with antioxidant and anti-inflammatory effects	[249]
N-acetyl-L-cysteine (NAC)	TXNIP/NLRP3/IL-1β signaling pathway	General ROS inhibitor	Atherosclerosis, acute lung injury (ALI)	Decreases IL-1β production and protects against oxidative stress in cell models	[230, 250]
Bixin	TXNIP/PPARγ/NRF2	Scavenges ROS via NRF2 signaling pathway	EAE	Inhibits EAE severity in animal models	[252]
Canakinumab	Interleukin-1 pathway	IL-1β-specific neutralizing antibody	Cryopyrin-associated periodic syndromes (CAPS), Still’s disease, AD	Used in clinical practice; poor CNS penetration and high cost	[243]
Anakinra	Interleukin-1 pathway	IL-1 receptor antagonist	CAPS, AD, PD	Used in clinical practice; poor CNS penetration and high cost	[243]

Future Therapeutic Perspective

As discussed above, inhibition of NLRP3 offers a therapeutic potential by modulating neuroinflammation. Both direct NLRP3 inhibition and antioxidant treatment have demonstrated beneficial effects in several animal models of brain injury. However, the translational significance of these findings in humans is not completely understood. Currently, several NLRP3 inhibitors are under clinical investigations, promising strategies to modulate inflammation in brain disorders. For example, in a phase 1b open-label study, NT-0796, a selective NLRP3 inhibitor with brain penetration, was administered orally to healthy volunteers and patients with PD for 7 or 28 days. The treatment reduced systemic inflammatory markers, including C-reactive protein, IL-6, IL-18, and IL-1β. A phase IIa/IIb study in PD patients is currently in preparation [258]. Another compound, VENT-02, also characterized by high brain penetration, has completed a phase 1b clinical trial in individuals with mild to moderate PD [256]. Similar results were reported with the NLRP3 inhibitor ZYIL1, which is in a phase 1 study and designed to study safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy humans. The results indicate that single and multiple oral doses of ZYIL1 reduced systemic levels of IL-1β and IL-18. The compound somalix (IZD-334) is a reversible, oral, selective NLRP3 inhibitor currently under investigation in a phase 1b trial for patients with early idiopathic PD [259]. The selective, CNS-penetrant, oral NLRP3 inhibitor VTX3232 reduces IL-1β in human blood and is presently in phase 2a trials for PD [260]. Although these selective inhibitors have shown the ability to reduce systemic proinflammatory cytokine levels, the available evidence is currently limited to early-phase clinical trials. Consequently, their potential impact on disease progression in PD remains to be determined. Ongoing and future phase 2 studies will be essential to establish their clinical efficacy and therapeutic relevance. It is important to consider the potential NLRP3 inhibition in humans by drugs commonly used in the treatments of chronic diseases such as Glibenclamide and Pioglitazone, compounds that are widely prescribed, safe, and well tolerated by patients with diabetes mellitus. These drugs have been shown to inhibit NLRP3 activation in animal models of TBI and PD [235, 236] (Table 1).

Despite the potential of NLRP3 inhibitors to modulate inflammation in the brain, it is important to consider the systemic effects of these drugs. As mentioned above, the NLRP3 inflammasome is critical for innate immune response based in the detection of PAMPs and DAMPs released by bacterial, fungal and viruses. Therefore, prolonged or systemic inhibition of NLRP3 may compromise host immune responses, representing a potential limitation of this therapeutic strategy. In contrast, antioxidants represent a safe and well tolerated alternative with a potential role regulating inflammation. However, clinical studies specifically evaluating the role of antioxidants in the modulation of the NLRP3 inflammasome remain scarce. Notably, the synthetic antioxidant edaravone was approved in the US for the treatment of patients with ALS which improved survival and life quality of patients [257]. These observations suggest that antioxidant-based may offer modulatory effects on inflammation (Table 1).

Future results from clinical investigations are crucial to determine the potential of NLRP3 inhibitors for PD and other brain pathologies. In this regard, the possibility of the evaluation of safe and well-known antioxidants in the modulation of NLRP3 in humans must be considered.

Conclusion

The convergent pathology of disparate neurological disorders on the oxidative stress NLRP3 inflammasome axis presents a significant and exciting opportunity for therapeutic development. The consistent finding that disease-specific protein aggregates or injuries act as DAMPs that activate this shared inflammatory pathway across acquired and degenerative brain diseases argues for a paradigm shift in treatment strategies from a focus on disease-specific pathology to the modulation of a central inflammatory node. However, significant hurdles remain, particularly related to achieving adequate BBB penetration and overcoming the translational challenges highlighted by the off-target effects of some agents. The future lies in developing innovative delivery systems and conducting robust clinical trials to turn this promising preclinical evidence into effective, disease-modifying therapies for patients, ultimately transforming the treatment landscape into a wide spectrum of neuroinflammatory pathologies.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This work was supported by the Dirección General de Asuntos del Personal Académico, UNAM (DGAPA-PAPIIT, UNAM; Grant No. IN224425). The funder had no role in the design, data collection, data analysis, and reporting of this study.

Author Contributions

C.R.-C. and A.M.M.-T. had the idea for the article. All authors wrote the first draft of the manuscript, commented on previous versions of the manuscript, critically revised the work, and read and approved the last version of the manuscript. J.M. raised funds and contributed to the writing and review of the manuscript.

Funding Statement

This work was supported by the Dirección General de Asuntos del Personal Académico, UNAM (DGAPA-PAPIIT, UNAM; Grant No. IN224425). The funder had no role in the design, data collection, data analysis, and reporting of this study.