Exploring pathogenetic mechanisms in subglottic stenosis: A narrative review toward an integrated molecular classification

Abstract

Subglottic stenosis (SGS) is a chronic fibroinflammatory condition that causes pathological narrowing of the air-way between the vocal cords and the trachea, with symptoms ranging from dyspnea to stridor and respiratory failure. The causes are heterogeneous: traumatic iatrogenic forms (such as prolonged intubation), autoimmune (e.g., granulomatosis with polyangiitis), post-viral (including COATS related to COVID-19), and idiopathic (iSGS), the latter affecting primarily adult Caucasian women with no obvious predisposing factors. All forms share a common pathogenetic core: epithelial damage, immune activation, chronic inflammation, and progressive fibrosis. Recent molecular studies, however, reveal that different variants of SGS exhibit distinct biological signatures, suggesting the existence of molecular subtypes with differentiated clinical courses. The emerging approach therefore aims for a biomarker-based classification for precision medicine. Future treatments may include targeted immunotherapies (e.g., IL-17A/IL-23 inhibitors), anti-fibrotic drugs, and epithelial regeneration strategies, alongside current surgical techniques to improve long-term prognosis.

1. Introduction

Subglottic stenosis (SGS) is a chronic fibroinflammatory disorder causing pathological airway narrowing between the vocal cords and the trachea, which can result in dyspnea, stridor, and even respiratory failure. Its etiology is heterogeneous and includes: (1) mechanical trauma, such as iatrogenic injury from prolonged intubation or tracheostomy, or exposure to caustic vapors/radiation; (2) inflammatory or auto-immune-related systemic diseases; (3) post-infectious causes, recently grouped under COVID-19 Associated Tracheal Stenosis (COATS) following SARS-CoV-2 infection; and (4) idiopathic subglottic stenosis (iSGS), defined by the absence of an identifiable cause [1] (Figure 1). iSGS is of particular interest due to its uncertain pathogenesis, high recurrence rate, and prevalence among adult Caucasian women, without prior intubation or autoimmune disease [2].

Figure 1.

Main etiological causes of subglottic stenosis.

The image shows the main causes of subglottic stenosis. Subglottic stenosis (SGS) has a heterogeneous etiology and can arise from various causes.

SGS variants differ in predisposing factors and course but share core mechanisms of epithelial injury, immune activation, chronic inflammation, and stromal fibrosis [3–5]. Histology shows mucosal inflammation, fibroblast proliferation, and fibrosis leading to airway narrowing. Current surgical/endoscopic treatments offer only temporary relief and high recurrence rate [6]. Pathogenesis involves epithelial barrier dysfunction, tissue-resident memory T cells (TRM) persistence, epithelial-to-mesenchymal transition (EMT), profibrotic fibroblast expansion and IL-17A–driven inflammation. Multiomic studies have revealed distinct molecular signatures, suggesting that SGS forms, despite a common anatomical phenotype, may be biologically distinct entities. These insights support a molecular classification to stratify patients and enable personalized therapies, with particular emphasis on iSGS, epithelial dysfunction, EMT, stromal remodeling, and immune dysregulation. Ultimately, biomarker-based approaches may redefine SGS as a heterogeneous, biologically driven disease with implications for diagnosis, prognosis, and treatment.

2. Methods

This work was conducted as a narrative review aimed at providing an integrative and critical synthesis of the current evidence on the molecular mechanisms underlying subglottic stenosis (SGS). A targeted literature search was performed using the PubMed/MEDLINE database to identify studies addressing the pathogenesis of SGS and laryngotracheal stenosis. Search terms included combinations of disease-related keywords (“subglottic stenosis”, “laryngotracheal stenosis”, “idiopathic subglottic stenosis”) and mechanistic concepts (“epithelial barrier”, “epithelial–mesenchymal transition”, “fibroblast activation”, “immune response”, “IL-17”, “TGF-β”, “transcriptomics”, “single-cell RNA sequencing”). Searches were limited to English-language publications. Priority was given to recent studies, translational research, and investigations employing molecular, transcriptomic, or single-cell approaches exploring epithelial dysfunction, immune circuits, and stromal remodeling in SGS. Additional relevant publications were identified through manual screening of reference lists from key articles and reviews in the field. No AI-generated content contributed to the scientific analysis, data interpretation, study design, or conceptualization of the manuscript. Given the narrative nature of this review, no formal systematic review methodology or predefined inclusion and exclusion criteria were applied. Instead, the selected literature was interpreted and synthesized to provide a conceptual framework integrating epithelial, immune, and stromal mechanisms in the pathogenesis of SGS.

3. Barrier damage: an “Immuno-Epithelial Disease”?

The airway epithelium, maintained by junctional complexes, ensures cohesion and barrier protection, while enabling polarization and differentiation into mucus-producing and ciliated cells essential for air-way clearance [7,8]. In iSGS, the airway epithelium is thinned, with loss of secretory/ciliated cells, expansion of pathological basal cells, increased CK5+/CK14+ expression, and reduced junctional proteins, supporting a role for epithelial dysfunction and impaired mucociliary clearance in disease pathogenesis [9]. Barrier failure is considered the initiating event, permitting microbiome translocation, immune activation, and fibroinflammatory remodeling [10]. iSGS is thus framed as an immunoepithelial disorder, sharing mechanisms with IPF and COPD, and pointing to therapeutic strategies targeting immune modulation and epithelial repair [11]. A pivotal study demonstrated intrinsic epithelial dysfunction in iSGS: scarderived epithelium showed reduced ciliated, goblet, and basal cells, with marked downregulation of junctional genes/proteins including E-cadherin (CDH1), Claudin-3/10, Occludin, and TJP1/2. Functional assays revealed decreased transepithelial resistance (TEER), increased FITC-dextran permeability, and impaired ciliary coverage. Protein analyses confirmed reduced E-cadherin and Occludin expression [12]. Beyond structural impairment, molecular profiling further linked epithelial dysfunction to clinical behavior. In a transcriptomic study of 56 women with iSGS and recurrent disease, high-relapse patients overexpressed genes linked to immune activation (IGHV4-34, IGHG4) and extracellular matrix (ECM) remodeling/fibrosis (COMP, NID2, MMP14, ADAMTS), whereas those with a lower relapse burden showed enrichment in ciliary function genes (CFAP210, DNAH11), suggesting preserved epithelial activity [13]. Collectively, these data indicate that epithelial barrier alterations are closely associated with recurrence risk. Epithelial abnormalities persist even after in vitro expansion, indicating intrinsic defects rather than changes secondary to inflammation or fibrosis. In both clinical specimens and experimental systems, barrier disruption facilitates microbial and antigen penetration into the lamina propria, thereby sustaining chronic immune activation and fibroblast-driven matrix remodeling—a pattern also described in chronic inflammatory mucosal conditions such as Crohn’s disease and atopic dermatitis. Consistently, grafting approaches aimed at restoring epithelial integrity have been associated with reduced recurrence rates, reinforcing the clinical relevance of barrier preservation [12]. A single-cell transcriptomic (scRNA-seq) study, integrated with animal models and advanced microbiological and immunological analyses, demonstrated profound epithelial depletion in iSGS, particularly of basal progenitor cells, along with marked immune infiltration characterized by CD8⁺ effector T cells and CD4⁺ Tregs. The residual epithelial cells exhibited a dysfunctional transitional phenotype with EMT features and mTOR pathway activation, indicating a shift toward mesenchymal identity. FISH and electron microscopy confirmed bacterial presence within the lamina propria exclusively in iSGS, not in controls, supporting microbial translocation as a key mechanism. Notably, while 16S rRNA sequencing revealed no major differences in microbiome composition compared to healthy subjects, this finding suggests that immune activation may be driven less by dysbiosis and more by abnormal microbial compartmentalization [14]. The mTOR pathway promotes collagen production and regulates CD4β T-cell differentiation, particularly Th17 subsets involved in profibrotic inflammation. Its inhibition with sirolimus (rapamycin) has proven effective in other CD4β T-cell-mediated fibrotic disorders, reducing fibroblast proliferation, collagen synthesis, and mitochondrial oxidative phosphorylation, while exerting immunosuppressive effects. Preliminary evidence shows that systemic sirolimus reduces surgical frequency in LTS patients, while sirolimus-eluting airway stents provide similar benefits in murine models with fewer side effects. Despite limitations of the bleomycin-induced model, these findings identify the mTOR pathway as a promising therapeutic target and support systemic and local strategies to slow LTS progression [15,16]. Murine models showed that subglottic fibrosis developed only in wild-type mice after epithelial injury, whereas germ-free or adaptive immunity–deficient mice (e.g., SCID) did not, indicating that both microbial exposure and adaptive immunity are required for disease onset. In vitro, T cells from the subglottic mucosa of iSGS patients proliferated in response not only to their own microbiota but also to microbiota from healthy donors, suggesting impaired immune tolerance in a dysregulated epithelial environment. Clinically, cricotracheal resection led to lower recurrence than endoscopic dilation, emphasizing the key role of epithelial integrity in therapy. These insights open avenues for future research, including epithelial–fibroblast co-culture models to clarify causal interactions, therapies aimed at restoring barrier function or transplanting healthy epithelium, and the identification of epithelial biomarkers predictive of recurrence and treatment response. Overall, the convergence of transcriptomic, experimental, and translational data supports a coherent immunoepithelial framework in which intrinsic barrier dysfunction, aberrant microbial localization, and maladaptive adaptive immunity interact to sustain chronic fibroinflammatory remodeling. While mechanistically compelling, much of the current evidence derives from cross-sectional molecular studies and experimental systems, and prospective validation in well-characterized clinical cohorts remains necessary to define its prognostic and therapeutic implications.

4. Epithelial-to-Mesenchymal Transition (EMT): Prognostic and therapeutic implications

A key mechanism linking epithelial injury to fibrosis is EMT, a process that converts damaged epithelial cells into matrix-producing cells, thereby contributing to collagen deposition and stromal thickening in fibrosing diseases, including iSGS. This process is mainly mediated by TGF-β signaling (Figure 2), as demonstrated in a canine model where anti–TGF-β treatment reduced tracheal stenosis and improved survival, highlighting its central role in fibrosis progression [17]. Gene expression analysis in stenotic tissue reveals consistent enrichment of EMT-related signatures and TGF-β-responsive pathways, alongside alterations in adherens junction, MAPK, and FGF signaling networks. Approximately 20 genes implicated in syndromic subglottic stenosis converge on these molecular circuits, suggesting partially shared pathogenic mechanisms with iSGS. Within this framework, EMT represents a key process linking epithelial destabilization to fibroblast activation and matrix deposition. Consistent with the hypothesis that epithelial dysfunction and stromal activation represent early pathogenic events, scRNA-seq of iSGS samples localized candidate gene expression across multiple cell populations. Approximately 15% of implicated genes were enriched in epithelial cells (EBP, FGFR2, GMNN), 15% in fibroblasts (ELN, FGFR1, TBX3) and 15% in endothelial cells (ADAMTSL2, FLNB, TONSL), while the remaining 55% showed broader expression patterns (COL5A1, GLI3). Notably, no predominant enrichment was observed in immune cells, suggesting that immune activation may not represent the primary initiating event [18]. Differential transcriptomic analysis revealed upregulation of fibrogenic/EMT-associated genes (WNT5A, MMP11, WNT2, THBS2, GREM1, MMP2, LOXL1, ITGB2, THY1, CCN4) and down-regulation of immune and epithelial homeostasis genes (IL6, CSF3, FOSL1, MYC, COL2A1, CHAD), consistent with barrier loss, stromal activation, and fibrosis in iSGS. Morphological evidence of EMT was provided by EPCAM⁺/S100A4⁺ double-positive cells in apical and glandular epithelial regions. Furthermore, PMEPA1, a TGF-β/EMT regulator, emerged as a potential prognostic biomarker: its overexpression correlated with shorter recurrence-free survival [19]. These findings further support EMT as a key contributor to iSGS pathogenesis and suggest that SGS may develop in genetically predisposed individuals in whom environmental or inflammatory insults trigger a maladaptive epithelial response, ultimately leading to irreversible subglottic fibrosis. Clinically, this framework highlights the potential value of early diagnostic strategies and targeted therapeutic approaches aimed at modulating TGF-β signaling, inhibiting EMT progression, or reprogramming activated epithelial and stromal compartments.

Figure 2.

Mechanisms of TGF-β–Induced Epithelial Barrier Dysfunction and EMT.

The image illustrates the molecular mechanisms by which TGF-β induces epithelial-to-mesenchymal transition (EMT) and compromises epithelial barrier integrity. In healthy tissue, epithelial integrity is maintained by junctional proteins such as E-cadherin, occludin, and claudins. Upon TGF-β receptor activation, Smad2/3 phosphorylation occurs, leading to complex formation with Smad4 and transcriptional activation of EMT-related genes. Concurrently, activation of the PI3K/Akt/mTORC1 signaling pathway contributes to junctional disassembly. These events result in loss of cell-cell adhesion, increased epithelial permeability, microbial translocation, and inflammation, ultimately promoting a dysfunctional tissue phenotype.

5. Fibroblasts in action: Architects of stromal remodeling in subglottic stenosis

Subepithelial stromal remodeling, driven by fibroblast activation, is a core pathogenic mechanism in subglottic stenosis. Through ECM deposition and the release of profibrotic cytokines, activated fibroblasts progressively thicken the airway wall and stabilize fibrotic architecture (Figure 3). TGF-β plays a pivotal role in sustaining this process by promoting fibroblast transition toward a myofibroblast phenotype and enhancing collagen synthesis, a signaling axis that appears to become progressively self-perpetuating in advanced disease stages.

Figure 3.

Immunological mechanisms involved in fibrosis in SGS.

The disease is characterized by chronic inflammation sustained by myofibroblast activation and extracellular matrix (ECM) deposition, driven by cytokines such as TGF-β, IL-17A, and INF-γ. Th1, Th2, and Th17 cells, along with γδ T lymphocytes and CD8+ TRM (resident memory T cells), contribute to this process through the release of profibrotic cytokines (INF-γ, IL-4, IL-17A). Macrophage polarization toward the M2 phenotype plays a further role in fibrotic progression. Latent infections and the persistence of TRM cells maintain a state of chronic activation, fueling the inflammatory-fibrotic cycle.

Karagiannidis et al. [20] reported markedly elevated TGF-β1 mRNA expression in post-intubation and stent-induced stenosis, with immunohistochemical localization in the subepithelial ECM. These tissues also showed CD4β TGF-β1–positive lymphocytes, likely Tregs, fostering a fibrogenic immune environment. Subepithelial α-SMA⁺ myofibroblast and collagen accumulation, with proliferation largely confined to the basal epithelium, indicated advanced, structured, non-proliferative fibrosis. In vitro, TGF-β1 activated fibroblasts despite mitomycin-C exposure, underscoring the limits of antiproliferative therapies. Together, these findings shifted the conceptual framework of benign subglottic stenosis from a reactive proliferative disorder to a chronic, signaling-driven fibrosing condition sustained by persistent molecular crosstalk. Motz and Gelbard [21] highlighted pathological fibroblasts as key drivers of a TGF-β–mediated profibrotic microenvironment, sustaining fibroblast activation and ECM gene overexpression (COL1A2, COL3A1, FN1, MMP9). In iSGS, CD3β T-cell infiltration and IL-17A production synergize with TGF-β, while IL-4 via JAK/ STAT6 further enhances stromal remodeling, together creating a self-perpetuating cycle of fibrosis and airway narrowing. This immune-fibrotic profile of SGS resembles chronic fibrosing diseases such as idiopathic IPF and underscores the need for therapies targeting both fibrosis and immune dysregulation rather than purely mechanical or antiproliferative strategies [21,22]. Similar molecular patterns in iatrogenic SGS (ITS) support a shared model of chronic stromal fibrosis [23]. Microbiome and metabolomic analyses in ITS have further refined this model by demonstrating that persistent fibroblast activation, driven by epithelial injury, hypoxia and inflammation, is accompanied by carnitine depletion. Given carnitine’s role in mitochondrial metabolism, antioxidant defense and immune regulation, its reduction may contribute to sustaining fibro-inflammatory remodelling. These data extend the pathogenic framework beyond cytokine signaling, suggesting that metabolic reprogramming may represent an additional layer of stromal dysregulation [24]. Single-cell RNA sequencing by Direder et al. [25] revealed expansion of a profibrotic fibroblast subtype (FB_A) in iSGS, characterized by ECM gene upregulation (COL1A1, COL3A1, POSTN) and confirmed pathogenicity at the protein level. Fibrotic tissue also contained abundant plasma cells (up to 29.4%) linked to the MIF–CD74–CXCR4 pathway, as well as activated Schwann cells with a profibrotic profile. ECM remodeling showed dense fiber networks with TNC, SFRP1, and CTHRC1 upregulation, while altered interactions among fibroblasts, plasma cells, mast cells, and B cells established a self-sustaining profibrotic stromal niche. [25]. The CARE group mapped healthy and diseased subglottis/epiglottis, identifying a profibrotic fibroblast subtype (F4) enriched in iSGS, while regenerative F6 fibroblasts (AXIN2β, SLIT2β) were absent. RNA velocity analyses suggested a microenvironment-driven transition from F6 to F4 states, implicating the local inflammatory niche in fibroblast fate reprogramming. Concurrently, aberrant CD55β goblet cell–mast cell signaling and dysfunctional TGF-β/androgen responses within F4 fibroblasts contributed to a disturbed stromal network. A four-subtype iSGS classification was proposed: SUBSET3/4 with high stromal activity correlated with recurrence, while F4 predominance predicted aggressive disease; conversely, F6/F7 fibroblasts and E21 epithelial cells appeared protective. Importantly, this integrative cellular mapping moved the field beyond descriptive histology, enabling risk stratification models and highlighting actionable targets such as POSTN, TGF-β signaling, and the F6βF4 transition. On this basis, antifibrotic agents used in IPF, including nintedanib, pirfenidone, and SMAD/TGFBR1 inhibitors, have been proposed as potential therapeutic strategies [26,27]. Collectively, these converging data position fibroblasts not merely as matrix-producing effectors but as central regulators of immune, epithelial, and metabolic interactions within a self-reinforcing profibrotic niche. The clinical implications of this stromal heterogeneity remain to be fully established.

6. The role of immuno-epithelial circuits in tracheal stenosis

Chronic inflammation and immune dysregulation underlie tracheal stenosis in iSGS, ITS, and COATS, with diverse triggers converging on a persistent fibro-inflammatory process driven by epithelial, immune, and stromal interactions [28,29]. In iSGS, pathogenesis remains incompletely defined, but altered estrogen signaling and microtrauma have been proposed as contributing factors [30]. Scarred epithelium loses estrogen and progesterone receptor expression, while fibroblasts and immune cells retain them [31], potentially disrupting local immune regulation. Concomitant barrier dysfunction—characterized by reduced adhesion molecules, increased permeability, and ciliary loss [12]—suggests that hormonal imbalance and epithelial fragility act synergistically within a shared pathogenic axis. In ITS, mechanical injury initiates maladaptive inflammation. Transcriptomic profiling reveals hyperkeratinization and inflammatory signatures (CALML5, S100A7, KRT16), alongside impaired apoptotic and repair pathways (ATM, CASP8), indicating defective epithelial restitution rather than simple hyperproliferation [32]. β-defensins (DEFB4A, DEFB103A) act as chemoattractants sustaining inflammation, while keratinization pathways promote squamous metaplasia and impair mucociliary function. Resistance to retinoic acid signaling further limits repair, supporting retinoid-based therapeutic exploration in recurrent ITS and COATS [32]. These findings suggest that impaired epithelial restitution, rather than excessive proliferation alone, may represent a key driver of persistent inflammation across etiologies. In iSGS, epithelial–immune interactions display distinctive features. Pro-inflammatory CD55β goblet cells (E22), highly androgen-sensitive but weakly estrogen-responsive, may contribute to female predominance and interact with mast cells via ADGRE2, sustaining chronic immune activation. Although the immune infiltrate varies, epithelial–immune networks are consistently disrupted, with impaired proregenerative signaling such as abnormal MIF secretion, defining iSGS as an immune-mediated, epithelium-dependent disease [27]. Proteomic and molecular analyses further reveal overexpression of IGHG1, ARP2/3 complex genes, and LTA4H, implicating humoral immunity, cell motility and neutrophil recruitment [34], alongside increased metabolic activity consistent with immune activation and fibroblast hyperproliferation [35,36]. Platelet activation signatures and platelet-derived microparticles have also been implicated in perpetuating fibroblast cytokine production and fibrosis [33]. Epigenetic profiling further implicates DNA methylation changes, including hypermethylation of CpG regions such as HIVEP3 and altered BTD regulation, highlighting systemic–local interactions [35–42]. In parallel, proteomic clustering analyses delineate molecularly distinct inflammatory subgroups with potential prognostic relevance [43]. Together, these multiomic data reinforce the view that immune dysregulation in iSGS extends beyond simple cytokine imbalance, encom-passing metabolic, epigenetic, and stromal reprogramming components. However, the functional hierarchy among these alterations remains incompletely defined. A defining feature of iSGS is persistent mucosal immune memory driven by clonally expanded tissue-resident memory (TRM) T cells [44]. Scar tissue is enriched in CD8⁺CD69⁺CD103⁺ TRM expressing activation and cytotoxic markers, with clonally expanded TCRs recognizing viral antigens (CMV, EBV, influenza, Mycobacterium tuberculosis) and additional putatively autoreactive clones, suggesting antigen-driven and autoimmune mechanisms [45]. TRM persistence is maintained by TGF-β [46] and NOTCH signaling [47], creating a maladaptive immune niche that promotes chronic inflammation, epithelial dysfunction, and fibrosis. This framework redirects attention from transient inflammatory triggers toward sustained local immune memory as a key determinant of disease chronicity, providing a mechanistic rationale for complete resection strategies aimed at eliminating TRM reservoirs and for immunotherapies targeting TRM survival pathways [48]. Both iSGS and iLTS exhibit a sustained Th2 response, with IL-4–driven Th2 cells and M2 macrophages promoting collagen deposition [49–53]. In iSGS, a profibrotic S100A8/A9⁺ macrophage subset further enhances fibroblast collagen expression [54], while elevated IFN-γ levels suggest coexistence of Th2-mediated fibrosis with a Th1 component [35]. Unlike other fibrotic diseases, chronic iSGS does not show marked TGF-β upregulation, indicating more complex immune regulation than iLTS [55]. COATS shares transcriptomic features with idiopathic and iatrogenic forms, including persistent inflammation, epithelial dysfunction, and fibrogenesis [56]. Scar tissue shows increased pro-inflammatory (CXCL11, CCL8) and fibrogenic (MMP3, HAS1) gene expression, persistent antiviral signaling (IFI6, DEFB4A), down-regulation of protective epithelial genes (SLURP1, CRNN), and altered retinoid metabolism, suggesting impaired epithelial regeneration. These molecular alterations highlight potentially actionable pathways, including retinoid signaling and matrix remodeling mechanisms, although targeted therapeutic validation is still lacking [57]. Complementary analyses confirm localized active inflammation in iSGS scars, with overexpression of cytokines (IL-6, IFN-γ, CCL2) and fibrotic markers (COL1A1, FN1, αSMA), and identify biologically distinct patient subgroups despite limited clinical correlation [58]. Expanded CD8β TRM clones with strong individual clonality further support a role for tissue-resident immune memory in sustaining inflammation and fibrosis [59]. Clinically, repeated intralesional steroid injections improve symptoms and prolong surgery-free intervals, underscoring the contribution of reversible inflammation, though variable responses reflect underlying biological heterogeneity [60]. Overall, the available evidence supports a model in which immunoepithelial circuits function as dynamic and context-dependent networks integrating hormonal influences, local immune memory, metabolic reprogramming, and stromal activation. While this integrative framework helps explain clinical heterogeneity across etiologies, its translation into predictive biomarkers or targeted immunomodulatory strategies remains to be fully established.

7. Clinical implications and therapeutic perspectives

Subglottic stenosis, especially idiopathic SGS (iSGS), should no longer be considered a single clinical entity but as a molecularly diverse disorder with interconnected pathogenic pathways. In this context, therapeutic strategies are progressively evolving beyond traditional surgical approaches. Standard surgical options, such as dilation or resection may be complemented by epithelial-restoring startegies and anti-inflammatory approaches that directly target the mechanisms underlying fibrosis, opening the way to more targeted interventions addressing the inflammatory and fibrotic processes that contribute to air-way remodeling. Because fibrosis represents a central mechanism in the pathogenesis of subglottic stenosis, antifibrotic drugs already approved for other diseases have been hypothesized to have a potential therapeutic role in this condition. In experimental studies and limited clinical experiences, nintedanib and pirfeni-done have shown a favorable effect in reducing fibrosis and improving airway stenosis, although the current evidence remains preliminary and largely based on experimental models or limited clinical observations [61,62]. Based on the involvement of the IL-23/IL-17 axis, this pathway has been proposed as a potential therapeutic target. Anti-IL-17A monoclonal antibodies, such as secukinumab and ixekizumab, have demonstrated clinical efficacy in several immunemediated inflammatory diseases and could therefore represent a possible translational strategy in SGS, although specific clinical studies are currently lacking [63,64]. Another potential therapeutic target is the TGF-β signaling pathway, one of the major mediators of fibrotic processes and airway remodeling. However, the clinical application of strategies targeting this pathway in subglottic stenosis remains exploratory and will require further translational and clinical studies to assess their effectiveness [65]. Taken together, these therapeutic strategies targeting inflammatory and fibrotic pathways may represent the most immediately translatable directions for the development of medical treatments in SGS. Alongside these therapeutic perspectives, the complexity of the pathogenic pathways involved in SGS opens additional research directions. In this context, the identification of biomarkers and the development of molecular classification systems could enable patient stratification, prediction of recurrence risk, and the development of more personalized therapeutic strategies. Transcriptomic studies have already identified specific cellular subpopulations potentially associated with more aggressive disease phenotypes, suggesting a possible role for molecular profiling in prognosis and treatment planning. Future research should focus on longitudinal studies to clarify disease triggers, validate molecular subtypes, and identify early biomarkers of recurrence. At the same time, the development of more advanced preclinical models will be essential to improve the understanding of SGS pathogenesis and to evaluate new therapeutic strategies. Experimental animal models of laryngotracheal stenosis, including large-animal models, have demonstrated the ability to reproduce epithelial injury, inflammation, and fibrotic remodeling characteristic of the disease, providing a valuable platform for investigating wound-healing mechanisms and testing novel therapeutic approaches [66,67]. In parallel, more complex in vitro systems, such as airway organoids, can recapitulate the cellular architecture and multicellular interactions of respiratory tissues, offering new opportunities to investigate disease mechanisms and evaluate drug responses in physiologically relevant experimental systems [68].

8. Conclusion

Subglottic stenosis emerges from this review as a biologically heterogeneous, fibro-inflammatory disorder driven by a complex interplay between epithelial barrier dysfunction, immune dysregulation, and stromal remodeling, rather than a purely mechanical airway disorder. At present, surgical intervention remains the main therapeutic option to restore airway patency and control symptoms. Nevertheless, a growing body of molecular, transcriptomic, and single-cell evidence demonstrates that SGS—particularly idiopathic forms—comprises distinct biological endotypes, challenging the traditional anatomy-based view of the disease and supporting a paradigm shift toward an integrated, biomarker-driven molecular classification. Within this framework, molecular stratification holds promise for refining prognostic assessment and recurrence prediction, while fostering the development of mechanism-based therapies targeting epithelial dysfunction, immune pathways, and fibrotic remodeling. Integrating these molecular insights into clinical practice may ultimately enable precision medicine approaches capable of achieving more durable airway patency and improved long-term outcomes for patients with SGS.

Availability of data and material

No datasets were generated during the current study.