Pyroptosis-type I interferon crosstalk in inflammatory myopathies: An evidence-graded reciprocal regulatory model and translational implications

Inflammatory myopathies are clinically and molecularly heterogeneous autoimmune diseases in which sustained type I interferon (IFN-I) responses and inflammatory cell death both contribute to tissue injury, yet their functional relationship remains poorly integrated. We integrate patient, disease-model, and mechanistic evidence to propose an evidence-graded reciprocal regulatory model between pyroptosis and IFN-I. Self-DNA may initiate AIM2/inflammasome-caspase-1-GSDMD-mediated pyroptosis; pyroptosis and ongoing tissue injury may increase self-DNA release or cytosolic exposure, together with the release of damage-associated molecular patterns (DAMPs), thereby potentially engaging cGAS-STING-TBK1-IRF3 signaling and IFN-I production; sustained IFN-I may in turn alter subsequent pyroptotic susceptibility through IFNAR-JAK-STAT-dependent transcriptional priming. Importantly, the complete bidirectional regulatory model has not yet been directly demonstrated in human inflammatory myopathies. Model persistence is further shaped by IFN negative feedback, DNA clearance, mitochondrial homeostasis, and oxidative stress. Evidence converges most clearly in dermatomyositis (DM): anti-MDA5-positive DM shows convergence of neutrophil extracellular trap (NET)-derived DNA, macrophage pyroptosis, and lung inflammation, whereas anti-NXP2-positive DM provides human evidence for self-DNA-cGAS/STING coupling. In antisynthetase syndrome, immune-mediated necrotizing myopathy, and inclusion body myositis, the network appears more context dependent. We also outline a biomarker framework spanning DNA/DAMP burden, pyroptotic activity, and IFN-I responses, and discuss therapeutic opportunities at IFN/JAK, inflammasome/GSDMD, and cGAS-STING nodes. This model integrates cell death, DNA sensing, and interferon signaling into a testable framework for disease persistence, molecular stratification, longitudinal monitoring, and mechanism-based therapy in inflammatory myopathies. TAKE-HOME MESSAGE: The proposed Pyroptosis-IFN-I reciprocal regulatory model provides an evidence-graded framework linking inflammatory cell death, self-DNA sensing, and interferon signaling in inflammatory myopathies. By integrating disease-context specificity with biomarker and therapeutic evidence, this model may help explain persistent inflammation and molecular heterogeneity while providing a rationale for mechanism-based patient stratification and targeted therapeutic investigation.