Interferon‐β Triggers Z‐ DNA Binding Protein 1‐Mediated PANoptosis in T Cells of Anti‐Melanoma Differentiation‐Associated Protein 5 Antibody‐Positive Dermatomyositis

ABSTRACT To investigate the role of PANoptosis activation in anti‐melanoma differentiation‐associated protein 5 (MDA5) antibody‐positive dermatomyositis (anti‐MDA5+ DM). Transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from 40 patients with anti‐MDA5+ DM and 10 healthy controls (HCs) was performed. The PANoptosis signature score was constructed using single sample gene set enrichment analysis based on the mean enrichment scores of the pyroptosis, apoptosis and necroptosis gene sets, and the clinical associations of the PANoptosis signature score in patients with anti‐MDA5+ DM were evaluated. PANoptosis markers were analysed via western blotting, and the regulatory mechanism of PANoptosis activation was studied in Jurkat cells in vitro. Transcriptomic profiling demonstrated overactivation of the PANoptosis signalling pathway in patients with anti‐MDA5+ DM. The PANoptosis signature score was positively correlated with inflammatory markers, type 1 interferon (IFN) signature score, disease severity and poor prognosis in patients with anti‐MDA5+ DM. Z‐DNA binding protein 1 ( ZBP1 ) was identified as a key PANoptosis‐related gene in anti‐MDA5+ DM. PANoptosis markers, including P‐MLKL, GSDMD‐N, cleaved caspase‐8, cleaved caspase‐3 and cleaved caspase‐7, were significantly upregulated in T cells from patients with anti‐MDA5+ DM. Functional assays demonstrated that IFN‐β induced PANoptosis activation in T cells in vitro, which was significantly attenuated following ZBP1 knockdown. PANoptosis overactivation was associated with disease severity and prognosis in anti‐MDA5+ DM. Our findings indicated that IFN‐β triggered ZBP1‐mediated PANoptosis in T cells, highlighting PANoptosis as a novel potential therapeutic target for anti‐MDA5+ DM.