Canonical activation of the NLRP3 inflammasome consists of two primary steps: priming and activation (Huang et al., 2021) (see Figure 1).

Ion flux plays a pivotal role in the activation of the NLRP3 inflammasome, and involves various ion channels that mediate critical ionic movements. For instance, the ATP-gated ion channel P2X purinoceptor 7 (P2X7) facilitates K+ efflux and Ca2+ influx, disrupting mitochondrial ion balance. This disruption generates mitochondrial reactive oxygen species (mROS), triggering NLRP3 inflammasome activation (Di Virgilio et al., 2017; Kong et al., 2022; Wang et al., 2020). Similarly, two-pore domain potassium (K2P) channels, such as ATP-induced two-pore domain weak inwardly rectifying K+ channel 2 (TWIK2) and THIK-1, enhance K+ efflux, which further facilitates NLRP3 activation (Wu et al., 2022; Di et al., 2018). Notably, THIK-1 is predominantly expressed in human microglia, suggesting that targeting this channel could be a viable approach for treating neuroinflammation (Rifat et al., 2024). Additionally, K+ efflux is essential for the activation of the NLRP3 inflammasome through the binding of NEK7 to NLRP3, a critical step in the activation process (Groß et al., 2016).

Another significant channel involved is the transient receptor potential melastatin type 2 (TRPM2), which is highly expressed in the brain. As a nonselective Ca2 + −permeable channel. TRPM2 exacerbates neuroinflammation and cognitive deficits through its role in NLRP3 inflammasome activation (Shao et al., 2021). This activation is largely due to increased intracellular Ca2+ concentration, which facilitates ASC recruitment to NLRP3 (Lee et al., 2012), leading to mitochondrial overload, damage, and subsequent reactive oxygen species (ROS) production (Murakami et al., 2012; Groslambert and Py, 2018), thereby promoting NLRP3 inflammasome activation.

Dysregulation of various organelles is considered a significant contributor to POCD by facilitating the activation of the NLRP3 inflammasome. This encompasses mitochondrial dysfunction, disturbances in lysosomes, and disintegration of the trans-Golgi apparatus.

Pyroptosis is a critical downstream event triggered by the NLRP3 inflammasome (Zhou and Abbott, 2021), representing a form of programmed cell death that is highly inflammatory and characterized by cell swelling and rupture of the plasma membrane (Ding et al., 2019). Central to this process is the GSDMD protein, which serves as the executor of pyroptosis. GSDMD is characterized by two distinct structural domains: the N-terminal domain, which is responsible for pore formation, and the C-terminal domain, which regulates protein activity (Yao et al., 2024). The activation of GSDMD is contingent upon cleavage by activated caspase-1 (Yao et al., 2024), which separates the pore-forming N-terminal domain from the C-terminal autoinhibitory domain. Following this cleavage, the GSDMD N domain relocates to the plasma membrane, where it oligomerizes to form large pores inducing pyroptosis. This pore formation facilitates the release of proinflammatory cytokines such as IL-1β and IL-18 and promotes the flux of ions such as calcium and potassium across the plasma membrane (Aglietti et al., 2016; Ding et al., 2016). The cell damage caused by pyroptosis leads to reactivation of the NLRP3 inflammasome, amplifying the impact of the inflammasome response to cellular threats. Research has demonstrated that microglial pyroptosis in the hippocampus mediates sevoflurane-induced cognitive impairment in aged mice via the ROS-NLRP3 inflammasome pathway (Zhou Y. et al., 2023). Furthermore, studies have shown that a deficiency in GSDMD results in a marked reduction in IL-1β release following inflammasome activation (Broz et al., 2020). Given its fundamental role in inflammasome signaling, targeting GSDMD to control pyroptosis and the subsequent release of proinflammatory cellular contents represents a novel approach for mitigating POCD (see Figure 2).

Autophagy is a fundamental self-protection mechanism that involves the degradation of dysfunctional organelles and the removal of abnormal proteins, and it plays a crucial role in maintaining cellular integrity and function (Fleming et al., 2022). The relevance of autophagy extends to the repair mechanisms of the nervous system, notably through the degradation of the NLRP3 inflammasome and the removal of substances that cause NLRP3 inflammasome activation [such as damaged mitochondria and mtROS (Yan et al., 2019; Zhou J. et al., 2023)], thereby limiting overactivation of the NLRP3 inflammasome to negatively regulate the NLRP3 pathway (see Figure 3).

Autophagy is also subject to regulation by various substances. AMP-activated protein kinase (AMPK) promotes autophagy, whereas the mammalian target of rapamycin (mTOR) signaling pathway inhibits authophagy (Bonam et al., 2024). The integration of LC3-II contributes to the elongation and closure of the phagophore membrane to form an autophagosome (Huang et al., 2018). Some activators of the NLRP3 inflammasome are transported for lysosomal degradation by endocytosis and phagocytosis. The phagophore fuses with the lysosome to form an autolysosome, in which the phagocytic substance is digested or degraded.

In addition, the selective elimination of abnormal mitochondria in the autophagy pathway, known as mitophagy, can target the removal of upstream events, leading to NLRP3 inflammasome activation (e.g., damaged mitochondria, mtROS). Mitophagy is mediated by ubiquitin or receptors. Ubiquitin-related mitophagy involves PINK1 (a serine/threonine-protein kinase)/Parkin (an E3 ubiquitin ligase) (Gao et al., 2015). In damaged mitochondria, PINK1 fails to be transported to the inner mitochondrial membrane, resulting in the accumulation of PINK1 dimers on the outer mitochondria and the recruitment of Parkin, which subsequently activates Parkin and induces mitophagy (Aerts et al., 2015; Gladkova et al., 2018). The second pathway is mediated by receptors including NIX/BNIP 3 L (Sandoval et al., 2008), BNIP 3 and FUNDC 1 (Chen et al., 2016). These receptors are expressed on the outer mitochondrial membrane and all contain LIR domains for interacting with the LC3 region, which are essential for initiating mitophagy (Li et al., 2023). Dephosphorylated FUNDC1 binds LC3 with high affinity to promote mitophagy (Liu et al., 2012), while BNIP3 and NIX promote mitophagy by stabilizing their interactions with LC3 through phosphorylation (Zhu et al., 2013; Rogov et al., 2017) (see Figure 4).

In the context of POCD, autophagy has emerged as a key protective mechanism. In sevoflurane anesthesia or surgically induced rat POCD models, the expression of AMPKα1, an important regulator of autophagy, was significantly downregulated (Yan et al., 2019). The activation of autophagy, achieved through the overexpression of AMPKα1, has been shown to alleviate cognitive impairments associated with surgery and anesthesia. This therapeutic effect is marked by an increase in the expression of autophagy markers such as LC-3-II and Beclin1 in the hippocampus and a decrease in p62 expression, indicating enhanced autophagic activity (Yan et al., 2019). Furthermore, recent studies have demonstrated that the inhibition of autophagy, characterized by a reduction in the LC3-II/I ratio and an increase in p62, is correlated with heightened activation of the NLRP3 inflammasome and exacerbated neuronal damage. The application of rapamycin, an autophagy activator, has been effective in reversing these adverse outcomes (Zhou J. et al., 2023), underscoring the potential of enhancing autophagy as a strategy for treating POCD. Sevoflurane significantly increases the levels of intracellular and mitochondrial ROS by 3.3-fold and 11.8-fold, respectively, which is accompanied by the accumulation of LC3B II/I and P62, decreasing mitophagy (Zheng et al., 2023). The use of an autophagy activator not only reduces reactive oxygen species (ROS) levels in cells and mitochondria but also blocks the elevated levels of LC3B II/I and P62, restoring mitophagy flux to normal levels (Zheng et al., 2023). These findings highlight the significance of autophagy in the prevention and treatment of POCD, suggesting that interventions aimed at promoting autophagic pathways could offer a promising avenue for mitigating the cognitive impairments associated with surgical interventions and anesthesia exposure (Chen et al., 2020).

Microglia, accounting for 10–15% of all brain cells (Dresselhaus and Meffert, 2019), are resident immune cells in the CNS that participate in CNS development, maintenance and response to damage and infection (Kent and Miron, 2024). In their resting state, microglia monitor their environment; upon activation, they transform into one of two polarization phenotypes depending on the activation state: the proinflammatory M1 phenotype (neurotoxic effects) or the anti-inflammatory M2 phenotype (neuroprotective effects). M1 microglial release proinflammatory cytokines (such as IL-1b, TNF-a, IL-18, and IL-6), chemokines, and reactive oxygen species (ROS), resulting in neuronal cell injury and BBB disruption (Brown and Vilalta, 2015). M2 microglia release anti-inflammatory cytokines IL-10, arginase (Arg-1) and chitinase-3 (Chil3) to maintain and repair neural tissue (Kanazawa et al., 2017) (see Figure 5).

The NLRP3 inflammasome is abundantly expressed in microglia. Activation of the NLRP3 inflammasome also influences the phenotypic transformation of microglia. Elevated NLRP3 levels are associated with the overexpression of the M1 microglial marker CD86, and the relative suppression of M2 microglial marker CD163 immunoreactivity (Ibrahim et al., 2023). For example, in models of Alzheimer’s disease in mice, overactive NLRP3 drives microglia to polarize toward the inflammatory M1 phenotype, which is characterized by upregulated caspase-1 and IL-1β, contributing to impaired spatial memory function (Ibrahim et al., 2023). These effects can be mitigated by deficiencies in NLRP3 or caspase-1 (Heneka et al., 2013). Furthermore, microglial autophagy not only inhibits NLRP3 activation as a negative regulator but also transforms microglia from a proinflammatory state (M1) to a favorable anti-inflammatory state (M2) (Wu et al., 2021), thus playing a protective role in the nervous system. However, microglial pyroptosis in the hippocampus mediates sevoflurane-induced cognitive impairment in aged mice (Zhou Y. et al., 2023). Therefore, transforming the microglial phenotype from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype is essential and represents a therapeutic approach for neurodegenerative diseases (Yao and Zu, 2020), including POCD.

In summary, when exposed to endogenous and exogenous stimuli, the NLRP3 inflammasome in microglia is activated, promoting the M1 phenotype and enhancing pyroptosis—a downstream event that leads to cell death and neuroinflammation, thus exacerbating the progression of neurodegenerative diseases. Autophagy serves as a countermeasure, mitigating cognitive deterioration by clearing inflammasome activators, reducing proinflammatory substances, and promoting the polaruzation of microglia toward the M2 phenotype.

Neurotransmitters are chemicals that promote neuronal communication and play an important role in synaptic plasticity, which is closely related to learning and memory, cognitive function, and brain injury recovery (Yang et al., 2023). Among neurotransmitters, gamma-aminobutyric acid (GABA) is the most important inhibitory transmitter in the mammalian brain (Samakashvili et al., 2011; Farrant and Nusser, 2005).Multiple types of GABA are present in the cerebrospinal fluid of AD patients (Samakashvili et al., 2011; Farrant and Nusser, 2005), and Wang L.-Y. et al. (2023) also found abnormal increases of GABA in the hippocampus of surgically exposed mice. Interestingly, the GABAergic system could promote macrophage mediated NLRP3 inflammasome activation (Krabbe et al., 2018). Lu-Ying Wang knocked out the astrocyte specific NLRP3 gene in mice and found that it could reverse TF-induced impulsive and cognitively impaired behavior, reduce GABA levels in cells, ameliorate NLRP3-related inflammatory responses, and restore hippocampal neuronal degeneration (Wang L.-Y. et al., 2023).

The NLRP3 inflammasome is a pivotal component in the development of POCD, making reducing of its activation and formation a critical aspect of POCD prevention and treatment. Various substances and methods have demonstrated potential in targeting the NLRP3 inflammasome, offering promising avenues for safeguarding cognitive function postsurgery.

Melatonin, known for its antioxidant properties and ability to protective agent against mitochondrial damage, plays a significant role in modulating inflammatory responses. It specifically targets the NLRP3 inflammasome and modulates the NF-κB pathway, which includes altering NF-κB phosphorylation, H3 histone acetylation, and NF-κB nucleation. These actions contribute to protecting against cognitive impairments in aged models (Zhu et al., 2023). The protein annexin-A1 Tripeptide (ANXA1), which is regulated by glucocorticoids, reduces the activation of the NLRP3 inflammasome across ages after surgery and improves cognitive dysfunction induced by neuroinflammation (Zhang et al., 2022). Similarly, vitamin D3 protects against POCD by deactivating the NLRP3 inflammasome and reducing the release of proinflammatory cytokines (Jiang J. et al., 2022). Lysine acetyltransferase 5 (KAT5) (Zhang Y. et al., 2023) assists in NLRP3 acetylation, promoting the oligomerization of NLRP3 and the subsequent assembly of the inflammasome, whereas NU 9056 blocks this process, offering the potential to treat NLRP3-associated diseases (Zhang Y. et al., 2023). Dexmedetomidine (DEX) is a widely used sedative agent in the clinic that mitigates the occurrence of POCD through multiple mechanisms, including inhibiting NF-kB, inhibiting NLRP3 inflammasome activation, regulating ASC expression, and promoting NLRP3 inflammasome degradation (Cho et al., 2022; Zeng et al., 2023). The components and techniques derived from traditional Chinese medicine relieve POCD. Helenine inhibits NLRP3-dependent ASC oligomerization and hinders the binding of NEK7 to NLRP3 (Fang et al., 2024), making it a promising drug for targeting the activation of the NLRP3 inflammasome. The ethyl acetate fraction of Bungeanum suppresses both the activation of the NLRP3 inflammasome and GSDMD-mediated pyroptosis in aging mice to ameliorate cognitive deficits (Zhao M. et al., 2021). Electroacupuncture (EA), an alternative acupuncture technique, suppresses the activation of the NLRP3 inflammasome via the inhibition of the NF-κB pathway, which is a potential technique for alleviating POCD (Sun et al., 2022; Wang W. et al., 2024).

These diverse strategies underline the importance of targeting the NLRP3 inflammasome as part of a comprehensive approach to prevent or treat POCD. By mitigating NLRP3 activation, it is possible to protect against cognitive decline associated with surgical procedures, improving the quality of life of patients undergoing surgery.

Autophagy, a critical cellular housekeeping mechanism, plays a vital role in removing damaged organelles and degrading aberrant macromolecular proteins. As a regulatory mechanism of NLRP3, autophagy limits the activation of the NLRP3 inflammasome by scavenging endogenous inflammasome activators, such as mtDNA, reactive oxygen species (ROS), dysfunctional mitochondria, inflammatory components, and cytokines (Biasizzo and Kopitar-Jerala, 2020; Pradel et al., 2020; Zhao S. et al., 2021). Furthermore, the role of mitochondria as a platform for NLRP3 and ASC recruitment (Qiu et al., 2022) underscores the importance of mitophagy in maintaining mitochondrial integrity and regulating NLRP3 activation.

Studies have illuminated the protective role of autophagy against cognitive impairments induced by anesthesia or surgery. For instance, Yeru Chen et al. demonstrated that mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction in aged rats (Chen et al., 2020). The use of Ac-YVAD-cmk, a specific caspase-1 inhibitor, has been shown to block caspase-1-dependent mitochondrial autophagy, reducing lipid peroxidation and mitochondrial ROS accumulation and alleviating sevoflurane-induced POCD (Zheng et al., 2023). Compounds such as Bergapten (BeG), a furocoumarin phytohormone with anti-inflammatory properties, have been found to suppress NLRP3 inflammasome activation and pyroptosis by promoting mitophagy and maintaining mitochondrial homeostasis (Luo et al., 2023). More specifically, BeG is involved in the regulation of mitochondrial gene expression and reactive oxygen metabolism in macrophages (Luo et al., 2023). Similarly, scoparone has been reported to enhance mitophagy, and mitigate reactive oxygen species (ROS) production and NLRP3 inflammasome activation, reducing inflammation (Feng et al., 2023). Scoparone also promoted the polarization of microglia from the M1 to the M2 phenotype (Ibrahim et al., 2023), which is involved in the protection of cognitive function. Polygala saponins inhibit NLRP3 inflammasome-mediated neuroinflammation via SHP-2-mediated mitophagy (Qiu et al., 2022). In addition, other studies have reported similar effects of drugs such as rapamycin (Zhou J. et al., 2023; Bonam et al., 2024), olaparib (Lu et al., 2024), TREM2 (Lu et al., 2024) and N-acetylcysteine (NAC) (Zhou Y. et al., 2023). Endocannabinoid receptor subtype 2 (CB2R) is a receptor involved in central nervous system immune regulation and plays a protective role in neurodegenerative diseases (Tiberi et al., 2022). JWH133, the CB2R agonist CB2R, promotes ubiquitination and autophagy-induced degradation of NLRP3 (Jiang F. et al., 2022). zDHHC12 is a member of the zinc-containing finger DHHC (Asp-His-His-Cys) type (zDHHC) palmitoyl S-acyltransferase (pat) family, which targets NLRP3 for palmitoylation, thereby promoting NLRP3 degradation through the chaperone-mediated autophagy (CMA) pathway (Wang L. et al., 2023).

In conclusion, enhancing autophagy represents a strategic approach to protect cognitive function following surgery and anesthesia by directly targeting the NLRP3 inflammasome and its upstream activators. The diverse range of compounds and mechanisms discussed underscore the potential for developing targeted therapies to prevent or ameliorate POCD.

GSDMD-induced pyroptosis, an inflammatory programmed cell death pathway, has been identified as a contributing factor to the cognitive impairments observed after the administration of volatile anesthetics such as isoflurane in aged mice (Fan et al., 2018). Addressing this pathway offers a promising strategy for alleviating postoperative cognitive dysfunction (POCD). GSDMD-induced pyroptosis, a novel inflammatory form of programmed cell death, is associated with cognitive dysfunction induced by the volatile anesthetic isoflurane in aged mice (Fan et al., 2018).

Necrosulfonamide (NSA), a chemical inhibitor that specifically targets GSDMD, prevents the formation of pyroptotic pores, thereby inhibiting pyroptosis (Rathkey et al., 2018). This mechanism has shown potential in mitigating neurological impairments induced by sevoflurane, suggesting a therapeutic approach for POCD through the pharmacological blockade of pyroptosis (Zhou Y. et al., 2023). Similarly, punicalagin, a complex natural polyphenol, acts as a pyroptosis inhibitor by impairing inflammasome-driven membrane permeability without affecting caspase-1 activity or the processing of IL-1β and GSDMD (Martín-Sánchez et al., 2016; Torre-Minguela et al., 2021). Its role in modifying plasma membrane fluidity can disrupt the assembly of N-GSDMD into the membrane, highlighting an additional avenue for pyroptosis inhibition (Torre-Minguela et al., 2021). Moreover, the antioxidant properties of punicalagin may further reduce pyroptosis by influencing the role of reactive oxygen species (ROS) in promoting N-GSDMD pore formation (Evavold et al., 2021). DUSP14, a regulatory protein, inhibits NLRP3 inflammasome-dependent pyroptosis, potentially serving as a critical mechanism for reducing neuronal injury and cognitive impairment in elderly rats (Que et al., 2020). After deacetylation, heat shock protein 90 (HSP90) has an enhanced protein binding ability and can bind to the NLRP3 protein to prevent its degradation (Piippo et al., 2018). The ability of ACY-125 to inhibit the deacetylation of HSP90 further demonstrates its potential to regulate microglial pyrosis by inhibiting NLRP3 at the molecular level (Lin et al., 2024). VX765 acts as a caspase-1 inhibitor that suppresses the expression of GSDMD and its cleaved form GSDMD-NT and reduces pyroptosis (Xu et al., 2019). Intermittent theta-burst stimulation in cerebral ischemic mice could improve nerve function by inhibiting neuronal pyroptosis and regulating microglial polarization via the NFκB/NLRP3 signaling pathway (Luo et al., 2022).

In summary, targeting GSDMD-induced pyroptosis is a multifaceted approach for mitigating POCD involving the inhibition of pyroptotic pore formation, the modulation of membrane permeability, and the regulation of inflammatory responses. These strategies highlight the importance of understanding cellular death mechanisms in developing effective treatments for POCD.

Rodents are the most common animal models for the study of postoperative cognitive dysfunction, and the establishment of such models involves two categories: simple anesthetic drug induction and complex surgical trauma. In addition, based on susceptibility to postoperative cognitive dysfunction, the rodent model also considers age, genetics, and preoperatively related cognitive dysfunction. There are also some relatively well-developed methods for assessing cognitive dysfunction in rodents, such as the fear condition test, the open field test, the Morris Water Maze test, the Y Maze test, and so on.

Through numerous animal experiments, scientists have identified a close relationship between the NLRP3 inflammasome pathway and POCD. This is since rodents share some similarities with humans in the NLRP3 inflammasome pathway. The NLRP3 inflammasome plays a key role in antimicrobial defense as well as in inflammatory diseases. In both mice and humans, NLRP3 is a highly sensitive but non-specific pattern recognition receptor that responds to perturbations of cellular homeostasis through a range of different stimuli (Sharma and Kanneganti, 2021). Activation of the NLRP3 inflammasome can be activated by stimuli including melanotin, uric acid crystals, beta-amyloid fibril, and extracellular ATP. The process is similar in mice and humans. Although the NLRP3 inflammasome in mice and humans is similar in basic structure and function, there may be differences in specific activation mechanisms. For example, K+ ion outflow is thought to be a common feature of many NLRP3 inflammasome (Xia et al., 2018), but in humans, it has also been reported that NLRP3 activation does not depend on K+ ion outflow (Schmacke et al., 2022). In addition, NEK7, as a mitotic kinase, allows interphase assembly and activation of the NLRP3 inflammasome in both humans and rodents (Sharif et al., 2019; Xiao et al., 2023), but their mechanisms may differ depending on whether this is achieved through activation of the K channel.

In summary, the NLRP3 inflammasome in rodents and humans is similar in basic function and structure, but there may be differences in specific activation mechanisms and interactions. These differences may result from physiological and metabolic differences between species, as well as adaptations to different environmental factors during evolution. Due to species differences, critically evaluating inflammasome research in cognitive dysfunction, including POCD and Alzheimer’s disease and related disorders, will be critical. In other words, it calls for the development of animal models that better mimic humans.

Bridging the gap between research and clinical applications, potential POCD biomarkers are something we need to focus on. The biomarkers of POCD are mainly divided into brain-derived biomarkers related to nerve injury and neurotoxicity and brain-derived biomarkers related to neuronutrition. Their functions are shown in Table 2.

There are few clinical trials or observational studies that provide direct clinical evidence for interventions such as the NLRP3 inflammasome or autophagy. Most of the studies were preclinical studies based on animal models and some circumstantial evidence. What we do know for sure is that some patients who have undergone anesthesia or surgery do show inflammation in their blood samples. In POCD patients who underwent total hip replacement, their inflammatory markers (including CRP, S-100B, IL-1β, IL-6, and TNF-α) were significantly elevated compared to non-POCD patients (Peng et al., 2013; Li et al., 2012), but these inflammatory factors were non-specific. Future studies should determine whether the NLRP3 inflammasome is involved in POCD in human patients.

In the process of advancing from preclinical research to clinical studies, ethical issues may be the most important problems we face in future research. Ethical concerns may relate to potential side effects, dosing issues, and patient variability (Figure 6). In preclinical studies, although a series of safety and efficacy evaluations have been conducted, after entering clinical trials, still needs to pay close attention to the potential side effects that may be brought by the drug, to ensure the safety of the subjects. Determining the appropriate drug dose is an important step in clinical trials. The pharmacokinetic properties of the drug need to be carefully studied, to ensure the efficacy and safety of the dose. Variability between patients may affect the efficacy and safety of the drug. In clinical trials, should fully consider the diversity of patient groups, and formulate corresponding research strategies.