Introduction

Asthma is a chronic respiratory disease that affects over 300 million people worldwide [1]. Its characteristic pathophysiological features include chronic airway inflammation, variable expiratory airflow limitation, airway hyperresponsiveness, and structural airway remodeling of the airways [1,2]. Despite significant progress in asthma research, the underlying mechanisms driving these alterations remain incompletely understood. Clinically, asthma manifests as cough, wheezing, shortness of breath, and chest tightness, which substantially reduce patients’ quality of life.

Although inhaled corticosteroids remain the foundational treatment for asthma, a substantial subset of patients exhibits steroid resistance or fails to achieve adequate disease control with standard therapies. Recently developed biologic agents targeting specific inflammatory pathways or immune components have provided new therapeutic options [2]. However, their high cost and limited efficacy in certain endotypes contribute to a persistent unmet clinical need. These limitations underscore the need for a more refined understanding of asthma pathogenesis and the development of novel therapeutic strategies.

Asthma is a multifactorial disease driven by a complex interplay between genetic predisposition and environmental exposures [3,4]. Advances in genomics have significantly expanded our understanding of asthma susceptibility genes and pathways. Among these, the 17q21 chromosomal locus has emerged as one of the most strongly associated regions with asthma [5]. This locus harbors a cluster of genes, including orosomucoid-like 3 (ORMDL3), GSDMA, GSDMB, and zona pellucida binding protein 2 (ZPBP2), and multiple single nucleotide polymorphisms (SNPs) within this region have been repeatedly associated not only with asthma risk but also with disease severity [5,6].

Recent studies have drawn attention to pyroptosis—an inflammatory form of programmed cell death—as a potential mechanism contributing to chronic airway inflammation in asthma [7]. Pyroptosis is characterized by the formation of membrane pores and the release of pro-inflammatory mediators, leading to intense inflammatory responses. In airway epithelial cells, this process can be triggered by various environmental stimuli, including allergens, respiratory viruses, and air pollutants [7]. Although pyroptosis may play a role in host defense, its excessive activation can cause tissue damage and drive chronic inflammation, which may link to asthma pathophysiology.

Gasdermin (GSDM) family, which mediates pyroptosis, includes several members such as GSDMA, GSDMB, GSDMC, GSDMD, and GSDME [8,9]. Among them, GSDMA and GSDMB have gained attention for their strong genetic associations with asthma susceptibility, particularly due to their location within the 17q21 locus [5,10]. GSDMD, in contrast, serves as a terminal effector of pyroptosis downstream of inflammasome activation and is under investigation for its role in airway inflammation.

This review provides a comprehensive overview of the emerging roles of GSDM proteins in asthma pathogenesis. It focuses on the structural characteristics and activation mechanisms of key GSDM members, as well as their genetic associations and pathophysiological mechanisms in asthma. Particular emphasis will be placed on the role of GSDMB in airway epithelial dysfunction and pyroptosis, the contribution of GSDMD to inflammatory processes, and the potential involvement of GSDMA and other GSDMs. Finally, we explore the therapeutic potential of targeting these pathways and their relevance to future precision medicine approaches in asthma management.

The GSDM family: structure, expression, and biological functions

The GSDM family comprises evolutionarily conserved proteins that serve as key effectors of pyroptosis, a highly inflammatory form of programmed cell death [8,11]. Upon activation, GSDMs form pores in the plasma membrane, leading to cell lysis and the release of pro-inflammatory intracellular contents. In humans, this family includes six paralogous genes—GSDMA, GSDMB, GSDMC, GSDMD, GSDME (also known as DFNA5), and DFNB59 (also known as pejvakin)—which share over 45% amino acid sequence homology in two highly conserved domains: the N-terminal (NT) and C-terminal (CT) regions [12].

Structurally, most GSDM consist of two functional domains: the NT domain responsible for pore formation via insertion into the cell membrane, and the CT domain that functions as an autoinhibitory segment [7,8]. In their resting state, these domains are held in an inactive conformation. Upon stimulation, inflammatory proteases—such as caspase-1, -4, -5, -11, or granzymes—cleave the interdomain linker, releasing the NT fragment. This active NT fragment translocates to the membrane, forms pores, and facilitates the extracellular release of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18, thereby initiating pyroptosis (Fig. 1) [7,8].

GSDMs are cleaved at multiple sites within the linker region, with cleavage specificity determined by the activating protease. For instance, streptococcal pyrogenic exotoxin B (SpeB) cleaves GSDMA, the house dust mite (HDM) protease Der p3 targets GSDMB, and granzymes A/B activate both GSDMB and GSDME [13-16]. This diversity of cleavage sites contributes to the physiological variability in GSDM activation across different tissue contexts. Notably, DFNB59 lacks the typical two-domain structure and, consequently, does not induce pyroptosis [8].

In terms of functional pathways, pyroptosis occurs via two primary mechanisms [8,12,17]. The canonical pathway is initiated by inflammasome activation (e.g., NLRP3), which subsequently activates caspase-1 to cleave GSDMs. The noncanonical pathway involves intracellular sensing of lipopolysaccharides (LPS) that directly activate caspase-4 and -5 (in humans) or caspase-11 (in mice), which in turn cleave GSDMs. In both cases, the activated NT fragments form membrane pores, resulting in cell lysis and the release of inflammatory mediators.

Beyond their role in lytic pyroptosis, GSDMs exhibit multifunctionality in immune regulation [12]. Upon pore formation, they can induce full lytic pyroptosis or, under sublytic conditions, facilitate cytokine release without complete cell lysis. Additionally, GSDMs can mediate non–pore-forming functions, such as promoting cell proliferation and cytokine secretion through alternative signaling pathways (Fig. 1). These proteins display tissue-specific expression and exert diverse biological roles depending on the cellular context (Table 1) [18]. For example, GSDMA is abundantly expressed in the skin, tongue, and stomach, and has recently been detected in airway epithelial cells [19]. GSDMB is uniquely expressed in gastrointestinal and respiratory epithelia and has been implicated in asthma-related inflammation [7,8]. GSDMC is expressed at lower levels in epithelial tissues such as the skin and lungs, with emerging roles in tumor necrosis [8]. GSDMD is highly expressed in innate immune cells such as macrophages, monocytes, and neutrophils, playing a central role in pyroptosis and IL-1β/IL-18 secretion [8,20]. GSDME is found in the cochlea, gastrointestinal tract, and neurons, where its cleavage by caspase-3 can switch apoptosis into pyroptosis [8,12]. In contrast, DFNB59 is not involved in pyroptosis and is predominantly expressed in auditory sensory cells, where it is linked to nonsyndromic hearing loss [21,22].

Such tissue-specific expression patterns underscore that GSDMs contribute to inflammation and immune regulation in a cell-type and context-dependent manner. In asthma, GSDM activation within airway epithelial cells, macrophages, and neutrophils may exacerbate inflammation, impair barrier function, and promote tissue remodeling [7]. Moreover, IL-33, IL-18, and IL-1β, which are released during GSDM-mediated pyroptosis, are potent activators of Th2 differentiation [23-25]. This is crucial as Th2-type immune responses characterize allergic diseases such as asthma. These cytokines promote Th2 differentiation either directly or through injury-associated signaling, thereby establishing a critical link between GSDMs and Th2-driven inflammation in the context of asthma.

Genetic associations between GSDMs and asthma susceptibility

Asthma is a heterogeneous chronic inflammatory disease caused by complex interactions between genetic predisposition and environmental factors [1,3]. Genome-wide association studies (GWAS) have identified numerous susceptibility loci, among which the 17q21 locus on the long arm of chromosome 17 stands out due to its repeated and robust associations with childhood-onset asthma [4,7,26]. This locus includes several tightly linked genes—GSDMA, GSDMB, ORMDL3, ZPBP2, Ikaros family zinc finger 3 (IKZF3), and leucine-rich repeat containing 3C (LRRC3C)—making it challenging to pinpoint the causal gene due to strong linkage disequilibrium across the region [5]. However, GSDMB has emerged as a key candidate gene within this locus, given its reported roles in pyroptosis, inflammation, and epithelial remodeling [27]. In contrast, other GSDM family members such as GSDMC, GSDMD, and GSDME have not shown significant genetic associations with asthma to date.

Both GSDMA and GSDMB have been linked to asthma susceptibility through SNPs [7,26,28]. Among the most extensively studied is rs7216389 (GSDMB), where the risk allele (T) is associated with an approximately 1.2-fold increased risk of asthma, particularly in childhood-onset cases [26]. This SNP is in high linkage disequilibrium with rs2305480 (GSDMB Pro311Ser) and rs11078928 (GSDMB), both of which are functionally relevant variants embedded within asthma-associated haplotypes [5,6,29]. rs2305480 is a nonsynonymous variant in GSDMB that results in a Proline-to-Serine substitution at position 311 [30]. Although it has been consistently associated with asthma susceptibility through GWAS, its direct functional impact on protein activity remains unclear [4,26]. Current evidence suggests that this variant may not substantially alter GSDMB's ability to induce pyroptosis [29]. On the other hand, rs11078928 is a splicing variant of GSDMB, where the protective allele (C) is associated with reduced asthma risk [7,29,31], whereas the risk allele (T) confers increased susceptibility [7,29].

A meta-analysis published in 2024 integrated data from over 20 global case–control studies, providing further support for the association between GSDMB polymorphisms and asthma susceptibility [27]. The analysis demonstrated significant associations of key GSDMB SNPs, including rs7216389, across Asian, European, and Hispanic populations, with particularly consistent effects observed in childhood-onset asthma. Notably, low heterogeneity across studies further reinforced the reliability of these associations.

There are only a few studies addressing GSDMA polymorphisms and their link to asthma. The intronic SNPs rs3859192 and rs8069202 were associated with a 4.4-fold and 3.7-fold increased risk of asthma, respectively, following early-life respiratory infections in Black children, with the risk alleles linked to reduced GSDMA expression in airway epithelial tissues [19]. In addition, other GSDMA SNPs—rs3894194, rs56030650, rs7212938, and rs7212944—have been implicated in childhood or adult asthma across diverse populations [28,29,32,33].

Beyond asthma susceptibility, GSDMB polymorphisms have also been linked to allergic inflammation. rs7216389 has shown a significant correlation with total serum immunoglobulin E (IgE) levels in children with asthma, suggesting that this SNP may influence IgE-mediated inflammatory responses [4,26]. This implies a potential role for GSDMB in the Th2-driven immunopathology of childhood asthma. In contrast, associations between GSDMA polymorphisms (e.g., rs7212938) and serum IgE levels have been inconsistent across populations. For instance, no significant correlation was found in a Jordanian cohort, while studies in Korean children suggested a potential link with higher IgE tertiles [28,34]. These findings suggest that GSDMB polymorphisms may have a more reproducible association with IgE-related immune responses across populations, although further comparative studies are warranted.

Table 2 summarizes key SNPs of GSDMA and GSDMB identified across multiple populations, highlighting their functional characteristics and associations with asthma-related phenotypes [8,19,26,28,29,31-41].

In summary, GSDMB stands out as the most critical GSDM gene associated with asthma susceptibility and clinical phenotype modulation. Its involvement is increasingly understood through multiple functional SNPs. While GSDMA has been implicated in asthma susceptibility—particularly through SNPs such as rs7212938 and rs3894194 identified in multiple populations—its functional contribution is less well characterized compared to GSDMB. Some studies have reported associations between GSDMA variants and bronchial hyperresponsiveness or childhood asthma. However, GSDMA polymorphisms do not appear to correlate with total serum IgE levels, suggesting its role may be independent of Th2-driven allergic inflammation. Further studies are needed to clarify the mechanistic impact of GSDMA variants on airway physiology and their interaction with GSDMB in the context of asthma endotypes.

Cytokine-driven regulation of GSDM expression

Since the GSDM family is involved in asthma pathogenesis, most studies have focused on genetic associations. In particular, research has examined how differences in gene expression and specific genetic variants contribute to asthma susceptibility and downstream effects such as pyroptotic activity and epithelial damage. However, recent studies indicate that GSDM expression is not exclusively determined by genetic variation [42]. Rather, their transcription can be dynamically and reversibly regulated by the airway's inflammatory microenvironment. This highlights a cytokine-mediated, nongenetic mechanism of regulation, positioning GSDMs as dynamic responders to environmental and immunological stimuli in asthma pathogenesis (Fig. 2).

For example, in gastric epithelial cells, transforming growth factor (TGF)-β1 stimulation induces the transcription factor LMO1, which binds to the GSDMA promoter and upregulates its expression [43]. This signaling pathway leads to increased apoptosis in gastric pit cells, suggesting GSDMA may act as a downstream effector of TGF-β1 signaling. Although observed outside the airway, these findings raise the possibility of similar mechanisms in bronchial epithelial cells under inflammatory conditions.

Recent experimental work using primary normal human bronchial epithelial cells evaluated the effects of cytokines on GSDM expression [42]. Upon stimulation with a panel of inflammatory cytokines, both GSDMA and GSDMB expression levels were significantly upregulated:

• • GSDMA was induced by: TNFSF14 (LIGHT), IL-5, IL-25, and TGF-β1

• • GSDMB was induced by: interferon (IFN)-γ, IL-4, thymic stromal lymphopoietin (TSLP), tumor necrosis factor (TNF)-α, TGF-β1, and LIGHT

These findings provide direct evidence that inflammatory cytokines can modulate GSDM expression independently of underlying genetic polymorphisms.

Beyond GSDMA and GSDMB, additional studies indicate that GSDMD expression is also regulated by pro-inflammatory cytokines. For example, TNF-α has been shown to induce GSDMD transcription via NF-κB signaling, while IFN-γ upregulates GSDMD expression through the STAT1–IRF1 axis, particularly in monocytes and macrophages [44,45]. These cytokine-mediated pathways suggest that GSDMD may be transcriptionally activated under type 1–skewed inflammatory conditions, further supporting its relevance in infection-driven or severe asthma phenotypes.

Collectively, these results highlight that GSDM expression in airway epithelial and immune cells is sensitive to distinct cytokine environments:

• • Th2 cytokines (e.g., IL-4, IL-5, IL-13, TSLP) may enhance GSDMA and GSDMB expression during allergic inflammation.

• • Th1 cytokines (e.g., IFN-γ, TNF-α), typically elevated during viral infections, may promote GSDMB and GSDMD expression.

• • Regulatory cytokines, such as TGF-β1, influence both GSDMA and GSDMB expression across epithelial contexts.

In conclusion, GSDM gene expression should be viewed as a flexible and context-dependent trait, shaped by both genetic and immunologic cues. This regulatory plasticity likely contributes to interindividual variability in airway inflammation and asthma severity, underscoring the potential for endotype-based classification and personalized therapeutic strategies targeting the GSDM pathway.

GSDMB in airway epithelial dysfunction and pyroptosis

GSDMB is the most strongly associated member of the GSDM family with asthma susceptibility. Its high expression in airway epithelial cells and its ability to induce pyroptosis, an inflammatory form of programmed cell death, suggest that GSDMB functions not only as a genetic susceptibility marker but also as a central effector in asthma pathogenesis.

GSDMB is a human-specific protein not expressed in rodents, which initially limited in vivo functional studies. However, recent advancements using transgenic mouse models (e.g., hGSDMBZp3-Cre) have enabled detailed investigation of its biological role [35].

In airway epithelial cells, GSDMB can be cleaved by a range of proteases. Known proteolytic activators include Der p3 from HDM, granzyme A released by cytotoxic T lymphocytes, neutrophil elastase, and caspase-1 [7,15,16]. These proteases liberate the NT domain of GSDMB (GSDMB-NT), which oligomerizes and inserts into the plasma membrane to form pores, thereby initiating pyroptosis. Among these stimuli, HDM—an environmental allergen implicated in allergic airway inflammation—may play a particularly critical role in asthma-related GSDMB activation.

This pyroptotic process extends beyond simple cell death; resulting in necrotic lysis of epithelial cells, release of pro-inflammatory cytokines and alarmins, and amplification of airway inflammation and hyperresponsiveness [35]. The consequent disruption of the epithelial barrier further facilitates antigen penetration and amplifies immune activation, triggering a cascade of downstream inflammatory and pathological responses [7,17].

Beyond inflammatory pathways, GSDMB also contributes to noninflammatory airway remodeling. Das et al. [5] demonstrated that GSDMB overexpression in bronchial epithelial cells leads to increased expression of TGF-β1, 5-lipoxygenase (5-LO), and matrix metalloproteinase-9 (MMP-9)—key mediators involved in airway remodeling features such as smooth muscle hypertrophy, fibrosis, and subepithelial thickening in asthma. Notably, these structural changes occurred even in the absence of overt inflammation, suggesting that GSDMB overexpression alone may be sufficient to initiate airway remodeling processes.

At the genetic level, alternative splicing of GSDMB contributes to functional diversity. The rs11078928 polymorphism disrupts the splicing acceptor site, resulting in the skipping of exon 6. This generates a shorter protein isoform of GSDMB consisting of 403 amino acids (commonly referred to as GSDMB-403), which lacks 13 amino acids compared to the full-length isoform, GSDMB-416. Notably, these isoforms differ functionally: GSDMB-403 exhibits significantly reduced pyroptotic activity, leading to attenuated inflammation and epithelial damage compared to GSDMB-416 [29,46]. Accordingly, rs11078928 is considered a protective variant that reduces asthma risk, underscoring the importance of isoform-specific functions in disease susceptibility.

The role of GSDMB also appears to be influenced by its nuclear localization. Das et al. [35] reported that nuclear translocation of GSDMB is required for TGF-β1-mediated transcriptional responses. A mutant lacking nuclear localization signals (GSDMB-ΔNLS) failed to support this function, suggesting that GSDMB may act as a transcriptional coactivator or regulator, despite lacking canonical DNA-binding domains.

The pathological functions of GSDMB have also been validated in vivo using hGSDMBZp3-Cre transgenic mice [5,39]. These mice exhibited spontaneous airway hyperresponsiveness and remodeling even without allergen exposure. Upon HDM challenge, they displayed hallmark features of asthma, including elevated Th2 cytokines, mucus hypersecretion, smooth muscle thickening, collagen deposition, and increased serum IgE levels.

In addition, GSDMB has been shown to upregulate chemokines such as CXCL6 (C-X-C motif chemokine ligand 6), CXCL17 (C-X-C motif chemokine ligand 17), CCL26 (C-C motif chemokine ligand 26, also known as eotaxin-3), and CCL28 (C-C motif chemokine ligand 28), promoting immune cell recruitment into the airway [5,47]. It also increases the expression of heat shock proteins (HSP60, HSP70), amplifying cellular stress and inflammatory responses.

Taken together, these findings establish GSDMB not only as a genetic marker but as a multifunctional mediator involved in pyroptosis, airway remodeling, epithelial barrier disruption, immune cell infiltration, and stress response amplification. This multifaceted role positions GSDMB as a promising therapeutic target in asthma.

GSDMA, GSDMD, and other GSDMs in asthma

In addition to GSDMB, other members of the GSDM family—particularly GSDMA and GSDMD—have also been implicated in the pathophysiology of asthma to varying degrees.

GSDMA, while primarily studied in skin-related conditions, has also been found to be expressed in lung tissues and airway epithelial cells [12,13]. Emerging evidence suggests that GSDMA expression may be inducible under specific inflammatory stimuli, and it may be cleaved by inflammasome components such as NLRP1 to initiate pyroptosis [14]. This activity could potentially impair epithelial barrier function and contribute to inflammation in the airways. The rs3859192 polymorphism within the GSDMA gene has been proposed as an expression quantitative trait locus, regulating gene expression in lung tissue and possibly modulating asthma susceptibility [28].

GSDMD is widely recognized as a key executioner of the canonical pyroptosis pathway, functioning as a central mediator of inflammatory cell death and innate immune responses [20,48,49]. Upon cleavage by caspase-1 or caspase-11 (caspase-4/5 in humans), the NT fragment of GSDMD oligomerizes and inserts into the plasma membrane, forming pores that induce pyroptotic cell death and facilitate the release of IL-1β and IL-18 [11,48].

This pore-forming mechanism is essential not only for antimicrobial defense but also for amplifying airway inflammation. Cleaved GSDMD fragments have been detected in bronchoalveolar lavage fluid from asthma patients, supporting the concept that GSDMD-mediated pyroptosis may occur even under noninfectious, sterile inflammatory conditions [20,43]. Given the pro-inflammatory actions of IL-1β and IL-18 in driving eosinophilic inflammation and airway hyperresponsiveness, GSDMD is increasingly recognized as an immunopathological driver in asthma [49]. Importantly, recent in vivo evidence supports a functional role for GSDMD in asthma. In an ovalbumin-induced murine asthma model, GSDMD silencing significantly reduced airway inflammation, mucus hypersecretion, and airway remodeling, further underscoring its potential as a therapeutic target [50].

Furthermore, environmental pollutants such as fine particulate matter (PM)2.5, ozone, and cigarette smoke have been shown to induce GSDMD expression and cleavage [51,52]. These pollutant-driven pyroptotic events can damage the airway epithelium and promote local inflammation. For instance, PM2.5 exposure has been shown to increase the expression of NLRP3, GSDMD, and IL-1β in murine nasal mucosa, resulting in epithelial injury [52]. Similarly, ozone exposure activates pyroptosis in lung cells through the TLR–NLRP3–GSDMD signaling axis [53]. Moreover, cigarette smoke has been reported to trigger GSDMD cleavage in both bronchoalveolar macrophages and bronchial epithelial cells in an NLRP3-dependent manner [51], further implicating GSDMD in environmentally triggered airway inflammation and asthma pathology.

Although GSDMC and GSDME have not been directly linked to asthma, they are known to participate in inflammatory responses and cell death pathways in immune cells and cancer models [8,12]. GSDME, in particular, can be cleaved by caspase-3, leading to a switch from apoptosis to pyroptosis [8]. This conversion may play a role in shaping the inflammatory environment under conditions where immune regulation is critical—such as in asthma.

In summary, beyond GSDMB, other GSDM family members may also influence distinct phenotypes of asthma through their involvement in inflammatory cell death pathways and epithelial injury. Further studies exploring their regulation, activation mechanisms, and tissue-specific functions will provide important insights and potentially support the development of novel therapeutic strategies targeting GSDMs in asthma.

Therapeutic implications and future directions

The GSDM, particularly GSDMB and GSDMD, has emerged as a central component in various aspects of asthma pathogenesis. Growing evidence suggests that therapeutic strategies targeting these molecules—such as inhibition of pyroptosis, preservation of epithelial barrier integrity, and suppression of inflammatory cytokine release—may offer promising alternatives for patients with asthma that is poorly controlled by conventional therapies.

GSDMB has been consistently identified in GWAS as a major susceptibility gene for asthma [5,26]. However, the precise mechanistic link between GSDMB and disease progression remains incompletely understood. Recent findings strongly indicate that the pathological function of GSDMB in allergic asthma lies in the ability of its GSDMB-NT to induce pyroptosis [35]. This suggests that inhibiting the pyroptotic activity of GSDMB-NT could represent a novel therapeutic strategy. While compounds such as disulfiram and necrosulfonamide have been shown to inhibit GSDMD-mediated pyroptosis [20,48], no agents have yet been identified that suppress GSDMB-NT–induced cytokine release or cell death. Thus, future studies should prioritize the identification of small-molecule inhibitors capable of targeting GSDMB-NT–mediated inflammatory pathways.

In parallel, strategies to inhibit GSDMD activation via the NLRP3 inflammasome and caspase-1 are being actively explored. Targeting these upstream regulators could simultaneously block pyroptotic cell death and downstream inflammatory cascades, thereby enhancing therapeutic efficacy. Such approaches may be particularly valuable in patients with severe asthma that is resistant to corticosteroids.

In addition, GSDM proteins are known to be highly responsive to environmental triggers such as air pollution, cigarette smoke, and common allergens. Therapeutic interventions that reduce or block these stimuli may help prevent GSDM activation and the subsequent cycle of epithelial barrier disruption and inflammation.

Based on current knowledge, several future research directions are warranted:

• • Comprehensive characterization of tissue-specific expression patterns and functional diversity of GSDM isoforms

• • Stratification of patient subgroups according to genotype-dependent differences in GSDM activity

• • Investigation of crosstalk between GSDM regulatory pathways and other pro-inflammatory signaling cascades

• • Long-term evaluation of safety and efficacy of GSDM-targeting agents using preclinical models

In conclusion, GSDM-mediated pyroptosis is increasingly recognized as a pivotal mechanism in asthma pathogenesis. GSDMB and GSDMD are critically involved in Th2-driven inflammation and epithelial barrier dysfunction, respectively. Inhibiting these molecules may offer a novel therapeutic option, particularly for patients with steroid-resistant asthma. Targeted modulation of the GSDM axis holds considerable potential for shaping the next generation of precision therapies in asthma.

Conclusions

The GSDM family—particularly GSDMA, GSDMB, and GSDMD—has emerged as an important player in the pathophysiology of asthma. These proteins are implicated in key features of asthma, including genetic susceptibility, Th2 cytokine signaling, epithelial barrier dysfunction, and steroid resistance. Emerging studies suggest that targeting GSDM-mediated pyroptosis could offer novel therapeutic options for patients with severe or poorly controlled asthma, while GSDM genotyping may enable precision medicine approaches by stratifying patients based on genetic risk and inflammatory phenotype.

However, further research is needed to clarify isoform-specific functions, cell type–specific roles, and the influence of environmental triggers such as air pollutants and cigarette smoke. Moreover, investigation of nonpyroptotic functions of GSDM may uncover previously unrecognized mechanisms and therapeutic opportunities. Taken together, the GSDM family represents a promising frontier in asthma research, with potential to drive the next generation of targeted treatments.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization: MM, GSC. Visualization: MM, GSC. Writing–original draft: MM, GSC. Writing–review & editing: MM, GSC. All authors read and approved the final manuscript.

Fig. 1.

Functional divergence of gasdermin (GSDM) proteins. GSDM family proteins elicit distinct cellular responses depending on their cleavage and activation pathways. Each GSDM member is cleaved by specific proteases, releasing the GSDM-NT, which binds to the plasma membrane and forms pores. This leads to pyroptosis or sublytic cytokine release. In contrast, non–pore-forming GSDMs are involved in cell proliferation or pore-independent cytokine secretion, contributing to inflammation regulation and tissue homeostasis. GSDM-NT, GSDM N-terminal; GSDM-CT, GSDM C-terminal; SpeB, streptococcal pyrogenic exotoxin B; IL, interleukin; LDH, lactate dehydrogenase; HMGB1, high mobility group box 1; ATP, adenosine triphosphate.

Fig. 2.

Feedback loop linking gasdermin (GSDM) expression to airway inflammation and inflammatory signaling. Schematic illustration showing how genetic regulation of GSDMA, GSDMB, and GSDMD expression contributes to airway inflammation. Elevated expression of GSDMs increases the production of inflammatory mediators, which in turn may amplify upstream gene expression through feedback signaling, thereby perpetuating the inflammatory loop in asthma pathogenesis.

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