Reactive oxygen species and metabolic checkpoints shape plasmacytoid dendritic cell fate in infection and autoimmunity.

Plasmacytoid dendritic cells (pDCs) are innate immune sentinels uniquely specialised in the rapid and potent production of type I interferons (IFN-I) during viral infection. While this capacity is essential for antiviral defence, sustained pDC activation is a central feature of numerous autoimmune and inflammatory disorders. Although the molecular pathways governing nucleic acid sensing and IFN-I induction have been extensively characterised, the metabolic and redox mechanisms that support, and limit pDC function remain incompletely understood. Emerging studies reveal that pDC activity is tightly linked to a specialised redox-metabolic programme involving mitochondrial respiration, reactive oxygen species (ROS), and endolysosomal signalling networks. In this review, we integrate current evidence to propose that pDCs operate within a tightly regulated redox window that permits effective acute antiviral responses but renders them vulnerable to metabolic stress and dysregulation upon chronic stimulation. We examine how mitochondrial fitness, NAD+ homeostasis, ROS dynamics, and endolysosomal redox control collectively influence pDC activation, resolution of inflammation, and pathogenic persistence. By reframing pDC biology through a redox-metabolic perspective, we highlight new conceptual insights into IFN-I-driven disease and identify potential therapeutic strategies to selectively modulate pathogenic pDC responses.