ZBP1 contributes to IFN-β-induced PANoptosis-related skeletal muscle cell injury in dermatomyositis.

Background: Dermatomyositis (DM) is a systemic autoimmune disease characterized by cutaneous manifestations and inflammatory skeletal muscle injury. Dysregulated type I interferon signaling and regulated cell death pathways may converge to promote myofiber damage. PANoptosis integrates core components of pyroptosis, apoptosis, and necroptosis, but its contribution to DM remains unclear. Methods: Transcriptomic datasets from DM skin and skeletal muscle were integrated to identify differentially expressed genes overlapping with a predefined PANoptosis-related gene set. Candidate core genes were prioritized using least absolute shrinkage and selection operator regression, random forest, and extreme gradient boosting. A four-gene PANoptosis-related risk score (PRS) was constructed and evaluated for discriminatory performance and associations with inferred immune cell composition. Adult human skeletal muscle cells (HSkMCs) were exposed to interferon-β (IFN-β), and PANoptosis-associated injury was assessed by transmission electron microscopy, western blotting, co-immunoprecipitation, Cell Counting Kit-8 assays, LDH release, and ROS measurement. Molecular docking and microscale thermophoresis (MST) were used to evaluate baicalin binding to ZBP1. Results: Eleven DM-associated PANoptosis-related genes were identified, and ZBP1, CD14, TLR3, and TNFSF10 were consistently prioritized. The PRS yielded an area under the curve of 0.9375, and high-PRS samples showed stronger innate immune and inflammatory transcriptional signatures. All four genes correlated positively with the inferred abundance of M1 macrophages and were upregulated in peripheral blood mononuclear cells from patients with DM. ZBP1 expression correlated positively with serum creatine kinase. IFN-β reduced HSkMC viability, increased LDH release, and induced ultrastructural and molecular changes associated with apoptosis, pyroptosis, and necroptosis. ZBP1 overexpression increased its association with RIPK3, caspase-8, and caspase-6, whereas ZBP1 knockdown attenuated PANoptosis-associated signaling, ROS accumulation, LDH release, and viability loss. MST confirmed direct baicalin-ZBP1 binding. Baicalin reduced ZBP1-associated protein co-precipitation and alleviated IFN-β-induced cellular injury. Conclusion: This study identified four candidate core PANoptosis-related genes associated with DM and developed a four-gene PRS model with strong discriminatory performance for distinguishing DM samples from controls. Mechanistically, ZBP1 may contribute to IFN-β-induced PANoptosis-like injury in HSkMCs by facilitating its association with RIPK3, caspase-8, and caspase-6. Baicalin may protect HSkMCs by directly binding to ZBP1 and attenuating these PANoptosis-associated protein interactions.