IFNγ and TNFα Driven IRF1-Caspase 8 Dependent PANoptosis Promotes Keratinocyte Death in Psoriasis Independent of ZBP1

Abstract Psoriasis is a chronic inflammatory skin disorder characterized by dysregulated keratinocyte proliferation, differentiation, and immune activation. While aberrant immune signaling is well established, the contribution of inflammatory cell death pathways remains incompletely understood. Here, we identify PANoptosis, an integrated form of programmed cell death encompassing pyroptosis, apoptosis, and necroptosis, as a central feature of psoriasis. Integrative analysis of bulk and single-cell transcriptomic datasets revealed consistent upregulation of PANoptosis-associated genes in psoriatic lesions, predominantly in keratinocytes. Functional studies demonstrated that interferon-γ (IFNγ), particularly in combination with tumor necrosis factor-α (TNFα), robustly induces PANoptotic gene expression and inflammatory lytic cell death selectively in keratinocytes. This process is characterized by activation of caspase-8, caspase-3/7, GSDME, and necroptotic mediators, along with release of interleukin 1β. Mechanistically, cytokine-induced PANoptosis is dependent on the JAK–STAT1–IRF1 signaling axis but occurs independently of ZBP1 and nitric oxide. Inhibition of individual cell death pathways fails to rescue cell viability, whereas pan-caspase or JAK inhibition significantly attenuates PANoptosis, highlighting its coordinated nature. Furthermore, cytokine-induced PANoptosis is associated with downregulation of key epidermal barrier genes, linking inflammatory cell death to barrier dysfunction. Clinically, PANoptosis-associated gene expression decreases following anti-psoriatic therapy, while persistent caspase-8 expression correlates with poor treatment response. Furthermore, knockdown of either Caspase 8 or IRF1 attenuates PANoptosis. Collectively, these findings establish cytokine-driven PANoptosis as a critical mechanism underlying keratinocyte death and inflammation in psoriasis and identify the JAK–STAT1–IRF1-Caspase 8 axis as a potential therapeutic target for modulating inflammatory cell death.