Diabetic kidney disease (DKD) is one of the most debilitating microvascular complications of diabetes mellitus, affecting approximately 20–40% of diabetic patients worldwide. It has emerged as the leading cause of end-stage renal disease (ESRD), imposing a severe socioeconomic burden on global healthcare systems (1, 2). The pathogenesis of DKD is complex, involving a cascade of metabolic dysregulation, oxidative stress, and chronic inflammation, which has been supported by both mechanistic and population-based studies (3–5). While the urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are standard diagnostic tools, they exhibit significant limitations in terms of early sensitivity and prognostic specificity (6–8). Thus, there is an urgent need for novel biomarkers that reflect the underlying molecular pathology of DKD.

Recent studies have highlighted the pivotal role of pyroptosis—a pro-inflammatory form of programmed cell death—in the progression of diabetic renal injury. This process is typically initiated via activation of inflammasomes, leading to cleavage of GSDMD by caspases (9). Upon activation by inflammatory caspases (such as caspase-1/4/11), GSDMD is cleaved into an N-terminal fragment that forms large pores in the plasma membrane. This leads to cell lysis and the massive release of pro-inflammatory cytokines, including IL-1β and IL-18 (10, 11). In the diabetic milieu, high glucose levels and advanced glycation end-products (AGEs) trigger GSDMD-mediated pyroptosis in essential renal cells, including podocytes, renal tubular cells, and glomerular endothelial cells, directly contributing to glomerular filtration barrier breakdown and interstitial fibrosis (12). Beyond renal pathology, GSDMD-mediated inflammation is implicated in other diabetic complications such as cardiomyopathy and neuropathic pain (13, 14). In addition, emerging evidence suggests that targeting GSDMD-related pathways may have therapeutic relevance in diabetic kidney disease (15). Despite the robust evidence from experimental models linking GSDMD to renal damage, clinical data evaluating its utility as a circulating biomarker in human DKD remain limited.

In this study, we measured serum GSDMD levels in patients with DKD, other kidney diseases, and healthy individuals. Our primary objective was to evaluate the correlation between serum GSDMD and clinical markers of renal function (e.g., UACR, eGFR) and to assess its potential as a promising biomarker for DKD assessment.

In this cross-sectional observational study, we identified significantly elevated serum GSDMD levels in patients with DKD. Notably, circulating GSDMD concentrations correlated closely with well-established renal injury biomarkers, including UACR, CREA, BUN, and eGFR, and increased progressively with DKD severity. A key finding of this study is the strong association between serum GSDMD and UACR, which underscores a direct link between GSDMD and albuminuria—a hallmark of glomerular barrier dysfunction and a pivotal predictor of DKD progression. The observed relationship implies that GSDMD may serve as a surrogate indicator of ongoing inflammatory cell injury and structural renal impairment in DKD. Moreover, the inverse correlation between GSDMD levels and eGFR corroborates its association with renal function deterioration, further reinforcing the utility of serum GSDMD in stratifying DKD severity and evaluating disease status. Importantly, our data suggest that the association between GSDMD and renal impairment is particularly pronounced within the inflammatory milieu characteristic of diabetes. Although the non-DKD group exhibited more severe reductions in eGFR and higher CREA levels, serum GSDMD concentrations remained lower than those observed in DKD patients. This observation implies that GSDMD elevation is not merely a consequence of reduced filtration capacity but is closely linked to diabetes-associated inflammation.

Multivariate logistic regression analysis further validated serum GSDMD as an independent factor associated with DKD, supporting its potential as a clinically relevant biomarker for renal injury in diabetic patients. Our study provides novel insights by demonstrating the independent association of serum GSDMD with DKD. While GSDMD exhibited moderate specificity (62.13%), its high sensitivity (97.30%) underscores its value as a potent ‘rule-out’ screening tool to prevent missed diagnoses. The diagnostic performance of GSDMD (AUC: 0.847) was notable, and its combination with traditional indicators yielded a significantly higher AUC of 0.933. This demonstrates that GSDMD provides incremental diagnostic value as a vital complement to existing markers, reflecting the early inflammatory and pyroptotic damage central to DKD progression.

Our findings are consistent with recent experimental studies linking pyroptosis to diabetic kidney injury. GSDMD is a well-established executor of pyroptosis, activated via cleavage by inflammatory caspases such as caspase-1 and caspase-11 (16, 17). The cleaved GSDMD-N fragment forms membrane pores, leading to cell lysis and release of proinflammatory mediators like IL-1β and IL-18 (10, 11). In the context of DKD, high glucose levels, advanced glycation end-products (AGEs), and oxidative stress can activate inflammatory signaling pathways, including the NLRP3 inflammasome, resulting in caspase-1 activation and subsequent GSDMD-mediated pyroptosis in renal cells such as podocytes and renal tubular epithelial cells (12, 18).This GSDMD-mediated pyroptosis contributes to the structural and functional deterioration of glomeruli and renal tubules, promoting the initiation and progression of DKD (11). Our study shows that serum GSDMD concentrations are significantly elevated in DKD patients and correlate with key renal function parameters. Consistently, a recent prospective cohort study reported that circulating GSDMD levels were increased in uremic patients and were associated with disease prognosis, supporting the clinical relevance of serum GSDMD as a marker of renal injury severity (19).

Moreover, the potential of GSDMD as a therapeutic target in DKD is increasingly recognized. For example, dapagliflozin has been shown to attenuate skeletal muscle atrophy in diabetic nephropathy mice by suppressing GSDMD-mediated canonical pyroptosis, highlighting its role beyond that of a biomarker (15). In parallel, upstream metabolic regulators such as AMPK have been proposed as therapeutic targets in diabetic nephropathy due to their capacity to modulate inflammatory and cell death pathways, including pyroptosis, further supporting the translational relevance of targeting GSDMD-associated signaling networks in DKD (20).

Several limitations of this study should be acknowledged. First, due to the cross-sectional design, a definitive causal relationship between elevated serum GSDMD levels and the development or progression of diabetic kidney disease cannot be established. Consequently, these findings demonstrate a clinical association rather than causality; longitudinal studies are required to determine whether GSDMD elevation precedes the decline in renal function. Second, this was a single-center, hospital-based study employing a convenience sampling strategy, which may limit the generalizability of the results to broader populations, including different ethnic groups and clinical settings. Potential selection bias inherent to this study design cannot be fully excluded. Third, the diagnosis of DKD was based on established clinical criteria rather than renal biopsy confirmation, which might allow for overlap with other subclinical or mixed renal pathologies. Furthermore, upstream inflammasome components and downstream cytokines were not measured, limiting detailed mechanistic insight into the molecular pathways involved. Therefore, prospective studies on pyroptosis-related signaling pathways are warranted to further elucidate these mechanisms. Although an a priori sample size calculation indicated adequate statistical power, larger multicenter prospective studies are still warranted to validate these findings and to assess the prognostic value of serum GSDMD. Finally, serum GSDMD was measured using a chemiluminescence-based assay without direct methodological comparison to ELISA, meaning absolute concentration values should be interpreted with caution.

Despite these limitations, our study provides preliminary clinical evidence supporting the association between serum GSDMD and diabetic kidney disease, offering a foundation for future multicenter validation.

In summary, this study demonstrates that serum Gasdermin D (GSDMD) levels are markedly elevated in patients with diabetic kidney disease and independently correlate with established renal injury markers, including UACR and eGFR. These findings suggests that GSDMD may serve as a sensitive complementary biomarker for assessing inflammatory kidney injury in diabetes, with potential utility for early detection and risk stratification. Although this study is cross-sectional and single-center, and causality cannot be established, it provides a strong foundation for prospective, multicenter investigations to validate the prognostic and mechanistic relevance of GSDMD in DKD.