Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by immune dysregulation, progressive fibrosis, vasculopathy, and multiorgan involvement. Although the pathological hallmarks of SSc have been extensively described, the inflammatory mechanisms that drive disease progression remain incompletely understood. Increasing evidence suggests that innate immune activation and inflammatory cell death may contribute to tissue injury and fibrosis in autoimmune diseases. Pyroptosis is a highly proinflammatory form of programmed cell death mediated by inflammasome activation and is typically accompanied by the cleavage of gasdermin proteins and the release of inflammatory cytokines, particularly interleukin-1β (IL-1β). Among the known inflammasome pathways, absent in melanoma 2 (AIM2) is a cytosolic DNA sensor that recognizes double-stranded DNA and triggers inflammasome assembly, leading to downstream pyroptotic signaling. However, the activation status and clinical relevance of AIM2 inflammasome–mediated pyroptosis in SSc have not been fully clarified. In view of this gap, the present study was designed to systematically investigate the AIM2-mediated pyroptosis pathway in patients with SSc and to evaluate its association with clinical characteristics and disease phenotypes.

A total of 36 SSc patients and 36 age- and sex-matched healthy controls (HCs) were enrolled. Peripheral blood mononuclear cells (PBMCs) were collected from all participants to assess the expression of key components involved in the AIM2-mediated pyroptosis pathway. The mRNA expression levels of these pathway-related molecules were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR), and the corresponding protein expression levels were evaluated by Western blotting. To further reflect the downstream functional consequence of pyroptosis activation, serum IL-1β concentrations were measured using enzyme-linked immunosorbent assay (ELISA). The relationships between pathway activation and clinical parameters were analyzed using Spearman’s correlation analysis. In addition, subgroup comparisons were performed according to different antibody profiles and renal function status in order to explore the clinical heterogeneity associated with AIM2 pathway activation. Receiver operating characteristic (ROC) curve analysis was also conducted to determine the diagnostic value of individual pathway-related markers and of a composite model incorporating multiple markers.

Compared with HCs, patients with SSc exhibited significantly elevated expression of all key molecules involved in the AIM2-mediated pyroptosis pathway in PBMCs at both the mRNA and protein levels. This overall upregulation was accompanied by significantly increased serum IL-1β concentrations, indicating enhanced activation of the pyroptotic signaling cascade in SSc. Correlation analyses demonstrated that serum IL-1β levels were positively associated with erythrocyte sedimentation rate (ESR), aspartate aminotransferase (AST), uric acid (UA), and modified Rodnan skin score (mRSS). These associations support a close relationship between AIM2-related pyroptosis and systemic inflammation, organ injury, and the severity of skin fibrosis in SSc. In contrast, serum IL-1β levels were negatively correlated with estimated glomerular filtration rate (eGFR) and disease duration. These findings suggest that increased pyroptotic activity may be linked to impaired renal function and may be more pronounced during earlier stages of disease. Consistent with these observations, subgroup analyses showed significantly higher AIM2 pathway activation in patients with reduced renal function, defined as eGFR < 90, as well as in patients positive for Scl-70 antibodies. These subgroup findings further support the association of AIM2-mediated pyroptosis with more severe or aggressive disease-related phenotypes.

ROC curve analysis was performed to evaluate the ability of pathway-related molecules to discriminate SSc patients from healthy individuals. Among the individual markers examined, GSDMD mRNA demonstrated good diagnostic performance, with an area under the curve (AUC) of 0.743. Notably, when multiple pathway markers were combined into a composite model, the diagnostic performance improved substantially, yielding an AUC of 0.968. This result indicates that a multiparametric model based on AIM2 pathway activation may provide greater discriminative value than any single marker alone.

The AIM2-mediated pyroptosis pathway is markedly activated in patients with SSc and appears to be particularly pronounced during the early phase of disease. Activation of AIM2 and its downstream effector IL-1β is closely associated with systemic inflammation, renal impairment, fibrosis severity, and clinically aggressive subtypes, including Scl-70 positivity. These findings support the view that AIM2-driven pyroptosis may participate in the pathogenesis of SSc and may represent a clinically relevant biomarker axis. Moreover, the strong diagnostic performance of the composite marker model suggests that AIM2 pathway–related molecules may have potential utility in disease identification. Overall, this study provides evidence that AIM2-mediated pyroptosis is closely linked to key clinical features of SSc and may serve as a potential biomarker and therapeutic target for early intervention.