The pathogenesis of AS involves multiple processes, including endothelial dysfunction, low-density lipoprotein accumulation and oxidation, monocyte and lymphocyte recruitment, smooth muscle cell migration and proliferation, proinflammatory cytokine activation, and platelet adhesion (Zeng et al., 2019). Notably, the augmented release of inflammatory cytokines primarily attributed to endothelial cells, macrophages, and smooth muscle cell pyroptosis or NLRP3 inflammasome activation significantly contributes to AS formation and development (Zhaolin et al., 2019). Specifically, NLRP3 inflammasome-dependent pyroptosis triggers endothelial dysfunction, thereby acting as a catalyst for AS in these cells (Sun et al., 2017). This highlights the crucial role of NLRP3 inflammasome in promoting the release of inflammatory mediators and contributing to the pathological changes associated with AS.

Exercise can reduce the inflammatory death of local endothelial cells, slowing the development of AS plaques (Xu et al., 2019). A study found that voluntary wheel running, a natural type of aerobic exercise in the murine model could decrease the protein levels of the inflammasome components and markedly inhibit the caspase-1 activity in endothelial cells within the aorta of mice fed with a high-fat diet (HFD) (Lee et al., 2020). Recently, another study has demonstrated that exercise-induced a significant downregulation of m6A modification and methyltransferase-like 14 (Yang et al., 2023). This protein binds to the m6A sites of nuclear paraspeckle assembly transcript 1 (NEAT1) and promotes NEAT1 expression through subsequent YT521-B homology domain-containing 1, which transcriptionally promotes NLRP3 expression and endothelial pyroptosis (Yang et al., 2023). As a result, exercise effectively inhibits NLRP3 expression and endothelial pyroptosis, preventing AS plaque formation (Yang et al., 2023). In addition, it is widely recognized that fibroblast growth factor 21 (FGF21), a well-established negative risk factor for AS expressed in the aorta, exerts inhibitory effects on NLRP3 inflammasome activity, thereby attenuating aortic pyroptosis to prevent AS development (Zeng et al., 2020). Interestingly, aerobic exercise increases FGF21 sensitivity while downregulating the expression of pyroptosis-related proteins mediated by NLRP3 inflammasome in the aorta (Li et al., 2022). These findings suggest that activated FGF21 may be involved in aerobic exercise inhibiting NLRP3 inflammasome-mediated pyroptosis in the aorta. However, the current study has not investigated whether exercise improved AS via inhibiting NLRP3 inflammasome and pyroptosis in these cells, which needs further research in the future.

Homocysteine (Hcy), a non-essential amino acid sulfur, is derived from methionine and is used for methylation of DNA/RNA methylation (Veeranki and Tyagi, 2013). HHcy refers to a condition where plasma Hcy levels exceed 15 μmol/L and has been associated with various diseases especially AS (Winchester et al., 2014). HHcy promotes the generation of ROS through mechanisms such as mixed disulfide formation and auto-oxidation (Veeranki and Tyagi, 2013; Winchester et al., 2014). Recent research has demonstrated that HHcy-induced activation of the NLRP3 inflammasome in macrophages contributes to vascular inflammation and AS by activating caspase-1-mediated pyroptosis (Wang et al., 2017). In addition, acid sphingomyelinase upregulation by Hcy promotes clustering of lipid rafts mediating the assembly of NADPH oxidase complex resulting in increased ROS generation followed by NLRP3 inflammasome activation leading to pyroptosis contributing towards the development of AS (Liu et al., 2022).

Although direct evidence is currently lacking regarding whether exercise specifically modulates NLRP3 inflammasome activation or pyroptosis about HHcy, it has been observed that exercise can lower Hcy levels (Liu et al., 2022). In a folate-restricted model of HHcy, exercise can reduce the increase in plasma Hcy levels by increasing betaine Hcy s-methyltransferase levels in the kidneys and promoting nonclassical remethylation to convert Hcy into methionine (Vincent et al., 2006; Neuman et al., 2013). Moreover, apart from reducing plasma Hcy levels, exercise holds the potential for mitigating Hcy-induced lipid peroxidation and ameliorating reductions in superoxide dismutase and catalase activity, both of which are implicated in the progression of AS (Neuman et al., 2013). These works suggest that exercise might also inhibit NLRP3 inflammasome activation or pyroptosis as a part of its overall impact on reducing HHcy-related complications. Given these findings, further investigation is warranted to explore whether exercise precisely influences NLRP3 inflammasome activation or pyroptosis and their role in HHcy management. Understanding this relationship could provide valuable insights into developing targeted interventions for individuals with elevated Hcy levels and associated CVD.

Obesity, commonly associated with chronic low-grade inflammation, is characterized by the pathological enlargement of adipose tissue (AT) primarily due to excess energy accumulation as fat (Spalding et al., 2008; Wada et al., 2017). Mice with HFD-induced obesity exhibit increased expression of caspase-1, ASC, and NLRP3. However, knocking out the Nlrp3 or Caspase-1 gene suppresses obesity-induced fat depot (Stienstra et al., 2011). Therefore, targeting the activation of NLRP3 inflammasome or pyroptosis represents a promising approach for improving obesity.

A study found that exercise decreased protein expression of inflammasome components (NLRP3 and caspase-1) in bone marrow-derived macrophages (BMDM) and AT isolated from mice with diet-induced obesity (Javaid et al., 2021). Another study investigated perform mice fed either a standard diet or an HFD and subjected to regular ET or RT and discovered that RT attenuated increased NLRP3 expression and reduced levels of IL-18 in isolated AT, while ET effectively reduced the expression of TNF-α and IL-18 in supernatant from AT, suggesting that exercise can reduce inflammasome activation in ATs and achieve systemic downregulation of inflammatory cytokines (Wada et al., 2017). Besides AT, endothelial dysfunction emerges early on in CVD associated with obesity (Stienstra et al., 2011; Wada et al., 2017). A study demonstrated that engaging in voluntary running while on an HFD led to a significant reduction in active caspase-1 levels within the endothelial cells lining the aorta when compared to sedentary mice on the same diet (Li et al., 2023). These findings indicate that voluntary running alleviates impaired blood vessel function via inhibiting NLRP3 inflammasome activation (Li et al., 2023). In addition to endothelial cells, exercise suppressed NLRP3 inflammasome activation as revealed by downregulated IL-1β and IL-18 in BMDM (Li et al., 2023). This body of research demonstrates that exercise exerts inhibitory effects on NLRP3 inflammasome activation across various cell types to ameliorate obesity.

It’s worth noting that a human study found that exercise reduces plasma IL-18 levels in obese individuals, indirectly suggesting the inhibition of the NLRP3 pathway through exercise to improve obesity (Stienstra et al., 2011). Furthermore, 8-week high-intensity and aerobic interval training (three times/week) in men and women with metabolic syndrome resulted in decreased IL-18 mRNA levels in abdominal AT and a numerical decrease in plasma IL-18 concentration (Stienstra et al., 2011; Stienstra et al., 2011; Stienstra et al., 2011; Stienstra et al., 2011). Similarly, a pilot study, conducted among thirty-seven obese individuals demonstrates that exercise intervention, primarily consisting of activities such as walking, jogging, and functional exercise circuits designed to enhance aerobic capacity and speed, leads to significant reductions in ASC mRNA expression levels when compared to the hypocaloric group without any form of exercise participation (Barrón et al., 2020). These findings indicate an inverse relationship between ASC mRNA expression and aerobic interventions. Another randomized controlled trial involving 36 obese inactive subjects further delineated the type of exercise intervention and demonstrated both HIIT and MICT significantly reduced NLRP3 gene expression in serum samples from all subjects, strongly suggesting that diversity intensity interval training can inhibit NLRP inflammasome in obese (Armannia et al., 2022).

Therefore, exercise is considered a crucial strategy for reducing inflammation and metabolic disorders associated with obesity. Further research will enhance understanding of the complex relationship between exercise and NLRP3 inflammasome, leading to more effective interventions for managing obesity-related diseases.

Diabetes is a metabolic disease that poses a significant threat to human health. Type 2 diabetes, a significant risk factor for both microvascular and macrovascular diseases, accounts for 90% of diabetes cases and is a leading cause of death, particularly due to coronary heart disease (Einarson et al., 2018). Inflammatory processes play a crucial role in the development of complications associated with diabetes (Roncero-Ramos et al., 2018). Recently, NLRP3 inflammasome and pyroptosis have emerged as key contributors to insulin resistance (IR) (Roncero-Ramos et al., 2018). Peripheral blood-derived macrophages from drug-naïve patients with type 2 diabetes show increased expression of NLRP3 and ASC along with caspase-1 activation and IL-1β maturation (Lee et al., 2013). In vivo and in vitro studies have reported that high glucose stimulates IL-1β secretion in pancreatic β cells, resulting in their death through the activation of NLRP3 inflammasome (Zhou et al., 2010; Wu et al., 2019). The various modes of activating the NLRP3 inflammasome are fundamental factors influencing its complex effects on the progression of type 2 diabetes (Chen et al., 2021).

Engaging in aerobic exercise can improve IR and reduce the expression of NLRP3 and IL-1β in individuals with type 2 diabetes in aortic tissue, suggesting its positive impact on IR by inhibiting NLRP3 inflammasome (Hassanpour Soleimani et al., 2021). HMGB1 is a major pro-inflammatory cytokine released as a result of pyroptosis (Biguetti et al., 2019). This work also found that exercise can reduce the secretion of HMGB1, which is significantly increased in individuals with diabetes and contributes to disease progression (Hassanpour Soleimani et al., 2021). Previous studies have shown that exercise has the potential to lower HMGB-1 levels in circulation and tissues of diabetic patients, possibly by inhibiting NLRP3 inflammasome activation and pyroptosis (Haß et al., 2022; Haß et al., 2023). Furthermore, exercise decreased circulating levels of IL-1, which may potentially protect against IL-1-mediated destruction of β-cells (Stumvoll et al., 2005). Although there is currently no direct evidence on whether aerobic exercise specifically affects NLRP3 inflammasome activation or pyroptosis and thus decreases levels of blood glucose, these findings highlight the significant role played by exercise in regulating IR through its impact on NLRP3 inflammasome and pyroptosis.

DCM is a distinct cardiac phenotype observed in diabetic patients characterized by structural changes such as cardiac hypertrophy, cardiomyocyte death, and fibrosis, as well as functional abnormalities (Sun et al., 2021). The molecular mechanisms underlying DCM involve various factors including hyperglycemia, IR, fatty acids, oxidative stress, mitochondrial dysfunction, inflammation, and endothelial dysfunction (Chen et al., 2020). In particular, inflammation is believed to be present in the early stages of diabetes and plays a crucial role in promoting DCM (Luo et al., 2017). Emerging evidence has verified that NLRP3 inflammasome-mediated cardiomyocyte pyroptosis is a key participant in DCM (Xie et al., 2020). Human diabetic hearts also exhibit elevated activation of the NLRP3 inflammasome and cardiac pyroptosis compared to non-diabetic heart tissues (Zhang et al., 2015; Xie et al., 2020). Moreover, high glucose levels (35 mM) significantly induce increased protein expression of NLRP3, caspase-1, and IL-1β accompanied by noticeable cardiomyocyte pyroptosis, leading to loss of contractile units and cardiac dysfunction (Zhang et al., 2015). In contrast, silencing the Nlrp3 gene ameliorates cardiac inflammation and pyroptosis and improves cardiac function by ameliorating cardiac inflammation and pyroptosis both in vivo and in vitro experiments (Chen et al., 2020).

Exercise intervention has been shown to effectively prevent and treat DCM by modulating the NLRP3 inflammasome. For example, the expressions of NLRP3, caspase-1-p20, caspase-1p20/caspase-1, and IL-1β were increased in the myocardium of HFD-induced obese mice (Lee et al., 2018). However, treadmill exercise inhibited these parameters (Sun et al., 2021). This demonstrates that exercise training can prevent obesity-induced cardiac inflammasome formation, pyroptosis activation, and pro-inflammatory response (Sun et al., 2021). In addition, recent studies in DCM mice have demonstrated that although exercise has a limited impact on interstitial fibrosis, it can effectively reverse cardiac dysfunction by reducing the activity of NLRP3 inflammasome and inhibiting pyroptosis (Takahashi, 2019; Zhang et al., 2019). Moreover, in DCM rat models, elevated expression levels of the P2X7 receptor, NLRP3, caspase-1, and serum IL-1β were observed in the myocardium (Wang et al., 2022). However, following a 12-week treadmill running regimen in these rats, improvements were observed in terms of collagen deposition, cell disorder, as well as the expression levels of NLRP3, caspase-1, P2X7 receptor, and IL-1β within their heart (Zhang et al., 2015). Similarly, aerobic exercise also can inhibit the thioredoxin interacting protein (TXNIP)/NLRP3 inflammasome pathway and alleviate endothelial dysfunction in atherosclerotic coronary arterioles (Hong et al., 2018). These findings suggest that aerobic exercise can effectively mitigate fibrosis in the hearts subjected to an HFD and inhibit the activation of the NLRP3 inflammasome and pyroptosis in the myocardium. The effectiveness of exercise intervention on the NLRP3 inflammasome depends on the duration and intensity of exercise (Hong et al., 2018; Khakroo et al., 2019). Chronic exercise with moderate intensity significantly decreases the expression of the NLRP3 gene and levels of IL-1β, and IL-18 cytokines in serum (Khakroo et al., 2019). Conversely, chronic exercise with high intensity leads to a significant increase in gene expression of NLRP3 and levels of IL-1β, and IL-18 cytokines in serum (Khakroo et al., 2019). Therefore, personalized exercise regimens are necessary as there are currently no available guidelines; further research is needed.

Hypertension is a potentially fatal yet preventable risk factor for CVD and accounts for the majority of cardiovascular mortality (Deussen and Kopaliani, 2023). Persistent inflammation plays a pivotal role in hypertension development, with activation of the inflammasome and pyroptosis being potential contributors to its onset (De et al., 2021). NLRP3 inflammasome activities have been implicated in various cell types associated with pulmonary hypertension, including pulmonary arterial smooth muscle cells, pulmonary artery endothelial cells, and systemic hypertension (Haß et al., 2023). Additionally, higher serum levels of IL-1β were observed in patients with hypertension compared to normotensive controls (Wu et al., 2022).

Exercise is commonly suggested as a lifestyle adjustment for individuals with hypertension due to various factors including inhibition of inflammation (Newman and Verdin, 2014; Chakraborty et al., 2018; Kong et al., 2021). β-Hydroxybutyrate (β-OHB) ester is primarily synthesized in the liver and transported to extrahepatic tissues, traditionally recognized as a crucial metabolic fuel during starvation periods (Newman and Verdin, 2014). Contemporary evidence indicates that ketone bodies like β-OHB can maintain physiological homeostasis by inhibiting NLRP3-inflammasome-mediated inflammation (Kong et al., 2021). Recently, a non-targeted metabolomics approach revealed nutritional intervention with β-OHB reversed the high salt-induced adverse effects including renal NLRP3-mediated inflammation, fibrosis, and hypertension (Chakraborty et al., 2018). Interestingly, exercise is associated with increased circulating levels of β-OHB (Luo et al., 2021). Therefore, exercise may raise β-OHB levels and subsequently inhibit renal NLRP3 inflammasome activation, thereby alleviating hypertension and preserving kidney function. Another in vivo study provided direct evidence of the impact of exercise training on the downregulation of NF-κB and NLRP3 pathways in the mesenteric artery of spontaneously hypertensive rats (SHR) (Luo et al., 2021), which revealed that three intensity training intensities from low to high significantly inhibited the expression of NLRP3 inflammasome component and NF-κB within the mesenteric artery and alleviate BP in SHR rat (Luo et al., 2021). In addition to the SHR rat model, Bal et al., 2022 discovered that regulated aerobic exercise also effectively reduces BP and suppresses protein expression of NLRP3, IL-1β, and caspase-1 in the heart within the deoxycorticosterone-acetate salt hypertension model. These findings from the diversity hypertension model demonstrate that exercise training effectively attenuates NLRP3 inflammasome activity, highlighting its potential as a therapeutic intervention for hypertension.

MI, a common condition, refers to the death of heart muscle cells caused by a blockage in the coronary arteries (Wang et al., 2020). Following a heart attack, inflammatory reactions occur, characterized by the release of inflammatory cells, cytokines, and chemical hormones (Mezzaroma et al., 2011; Wang et al., 2020). These processes contribute to cardiac dysfunction, damage to the heart muscle, and remodeling (Mezzaroma et al., 2011; Wang et al., 2020). Indeed, NLRP3 inflammasome and pyroptosis-mediated inflammation have been reported to contribute to MI progression (Sandanger et al., 2013). Sandanger et al., 2013 first showed an increase in NLRP3 inflammasome activity in the left ventricle of the heart after MI. Furthermore, it appears that interfering with NLRP3 inflammasome signaling can prevent and mitigate damage caused by MI (Sandanger et al., 2013).

The research has shown that exercise training can delay the onset of ischemic reperfusion injury and MI (Thomas et al., 2016). In other words, exercise acts like ischemia preconditioning, which stimulates beneficial cellular responses. Azam Ahmadi et al., 2022 found HIIT can effectively decrease heart injury and NLRP3 expression in rats with MI. Interestingly, dynamin-related protein 1 (Drp1), an essential mitochondrial fission protein, can activate NLRP3 inflammasome through ROS generation after MI (Ahmadi et al., 2022; Jiang et al., 2022). However, the Azam Ahmadi team’s work demonstrates exercise preconditioning (EP) in a short period did not affect Drp1 (Ahmadi et al., 2022), while inhibiting NLRP3 expression. This finding indicates that EP in a short period is required to inhibit NLRP3 inflammasome independently of Drp1; the reduction of NLRP3 can occur through other mechanisms (Jiang et al., 2022).

HF means that the heart is unable to pump sufficiently to sustain blood flow to meet the needs of the body (Sacco et al., 2014). It represents the advanced stage of various CVD, including myocarditis, MI, cardiomyopathy, hypertension, atrial fibrillation, valvular heart disease, alcohol abuse, and infection (Bracey et al., 2013). Recent studies on calcineurin transgene mice have shown elevated mRNA of NLRP3 and enhanced cleavage of caspase-1 along with cardiac hypertrophy and ventricular dilatation (Bracey et al., 2013; Napodano et al., 2023). Genetic ablation of NLRP3 or administration of IL-1 receptor antagonist has been found to attenuate cardiac inflammation and systolic dysfunction (Bracey et al., 2013; Zhang et al., 2014; Napodano et al., 2023). Additionally, activation of NLRP3 inflammasome has been observed in LPS-stimulated cardiac fibroblasts and myofibroblasts, suggesting that its potential contribution to myocardial dysfunction through NLRP3 inflammasome or pyroptosis (Zhang et al., 2014; Boza et al., 2016). Although more research is needed to fully understand how the NLRP3 inflammasome or pyroptosis contributes to HF pathogenesis and progression; recent studies indicate that targeting this pathway could lead to new treatments for this debilitating condition (Lu et al., 2022; Xin et al., 2022).

Studies have shown that EP can regulate the NLRP3 inflammasome, reducing downstream inflammatory cytokines and protecting the heart (Li et al., 2020; Ma et al., 2021; Zhang et al., 2022). Li et al., 2020 found that moderate-intensity EP is more effective in protecting cardiac function and inhibiting the expression of TXNIP, NLRP3, NF-ĸB p65, and caspase-1 in the heart. As expected with moderate-intensity exercise, 8 weeks of aerobic exercise at this level inhibited protein expression related to myocardial NLRP3/caspase-1/IL-1β signaling pathways in mice with myocardial hypertrophy (Ma et al., 2021). In addition, Sandanger et al., 2013 show that the NLRP3 inflammasome is upregulated in myocardial fibroblasts post-MI, and maybe a significant contributor to infarct size development during ischemia-reperfusion. These findings highlight the potential therapeutic value of moderate-intensity exercise for cardiovascular health. However, exhaustive exercise (EE), characterized by sustained high-intensity exercise commonly practiced by athletes and soldiers alike, may lead to adverse reactions such as myocardial inflammation. It is reported that EE can increase NLRP3 expression and induce cardiac dysfunction which can be mitigated by EP at different intensities (Zhang et al., 2015). Importantly, moderate-intensity EP has cardioprotective effects on ventricular systolic and diastolic functions, indicating its superior efficacy compared to other intensities (Zhang et al., 2014).

Importantly, a clinical trial with 54 HF patients showed that exercise increased ASC methylation, decreased IL-1β and ASC mRNA levels compared to the control group in plasma, suggesting that exercise may improve HF via epigenetic regulation of ASC (Butts et al., 2018). Recently, our research team has reported for the first time that NLRP3 inflammasome-mediated pyroptosis contributes to the pathogenesis of non-ischemic dilated cardiomyopathy in cellular, murine, and human models (Zeng et al., 2020). Furthermore, numerous studies have investigated exercise intervention in patients with dilated cardiomyopathy and have demonstrated its safety and efficacy in improving exercise capacity and quality of life among these individuals (Stolen et al., 2003; Beer et al., 2008). Consequently, it is meaningful to investigate whether exercise can exert inhibitory effects on NLRP3 inflammasome activation and subsequent pyroptotic cell death in dilated cardiomyopathy. Preliminary data suggest that exercise may effectively inhibit NLRP3 inflammasome activation in dilated cardiomyopathy (unpublished data).

Although these experiments indicate that exercise improves HF by inhibiting NLRP3 inflammasome activation, there is still debate (Butts et al., 2018). For example, previous work reported that exercise training consisting of three sessions per week lasting for 60 min each, including aerobic exercises, strength exercises targeting major muscle groups, and stretching exercises have no effect on serum levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-8, and monocyte chemoattractant protein-1) of patients with severe Chagas cardiomyopathy (Rodrigues Junior et al., 2020), suggesting that exercise training may benefit patients with severe Chagas cardiomyopathy independent of its impact on inflammasome (Rodrigues Junior et al., 2020).

Most studies suggest that exercise improves HF by inhibiting the activation of NLRP3 inflammasomes. Nevertheless, a minority of research suggests that engaging in activities like EE might potentially worsen the progression of HF. It is imperative for future investigations to thoroughly examine the role played by NLRP3 inflammasome activation in exercise-induced exacerbation of HF.