Granzyme K: A new frontier in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder driven by dysregulated adaptive and innate immunity and aberrant complement activity. Although complement activation facilitates immune‐complex clearance, excessive activation aggravates tissue injury. Granzyme K (GZMK), a serine protease primarily expressed by CD8 ⁺ T cells and natural killer cells, has emerged as a critical pathogenic mediator in SLE, particularly in lupus nephritis. Recent evidence indicates that GZMK can initiate a noncanonical complement‐activation pathway, impair vascular barrier integrity, shape IL‐7R ^low CD8 ⁺ T cell states, and amplify inflammation via fibroblast crosstalk. Elucidating these mechanisms is vital for understanding SLE progression and identifying precise clinical targets. This review systematically summarizes current research on GZMK in SLE, integrating insights from single‐cell transcriptomics and mechanistic studies. We examine GZMK's expression patterns, its multifaceted contributions to disease pathology, and its potential as a specific biomarker for disease activity. Finally, we evaluate the prospect of targeting GZMK through innovative therapeutic strategies, such as specific inhibitors, offering new avenues for clinical intervention.