Serum Gasdermin D Adds Value to FIB-4 for Identifying FAST-Defined High-Risk MASH in Patients with MASLD: A Cross-Sectional Study

Abstract Background Pyroptosis has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), but the clinical relevance of circulating gasdermin D (GSDMD) remains unclear. We investigated the associations of circulating GSDMD and interleukin-1β (IL-1β) with disease severity and evaluated their incremental value for identifying FAST-defined high-risk metabolic dysfunction-associated steatohepatitis (MASH). Methods This cross-sectional study included 130 patients with MASLD and 70 healthy controls. Patients with MASLD were classified as having low-risk (FAST ≤ 0.35, n = 67) or high-risk MASH (FAST > 0.35, n = 63). Serum GSDMD and IL-1β concentrations were measured by enzyme-linked immunosorbent assay. Associations with high-risk MASH were evaluated using multivariable logistic regression. Discrimination and incremental performance were assessed using receiver operating characteristic curve analysis, net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration analysis, and decision curve analysis (DCA). Results Circulating GSDMD and IL-1β concentrations were significantly higher in patients with MASLD than in healthy controls (both P < 0.001), and GSDMD concentrations were higher in patients with high-risk than low-risk MASH (P < 0.001). Higher GSDMD concentrations were associated with greater hepatocellular injury, inflammation, and fibrosis-related abnormalities. After adjustment for age, body mass index, glycated hemoglobin, triglycerides, and FIB-4, both GSDMD (OR, 1.032; 95% CI, 1.010–1.055; P = 0.004) and IL-1β (OR, 1.303; 95% CI, 1.018–1.668; P = 0.036) remained independently associated with high-risk MASH. GSDMD alone yielded an area under the curve (AUC) of 0.785. Adding FIB-4 to clinical factors increased the AUC from 0.746 to 0.889, whereas further incorporation of GSDMD and IL-1β increased the AUC to 0.916. The integrated model improved reclassification (NRI, 1.293; IDI, 0.362; both P < 0.001), showed acceptable calibration, and provided greater net benefit on DCA. Conclusions Circulating GSDMD was associated with liver injury, inflammation, fibrosis-related abnormalities, and FAST-defined high-risk MASH. GSDMD and IL-1β provided incremental information beyond conventional clinical factors and FIB-4, supporting their potential as complementary biomarkers for non-invasive risk stratification in MASLD.