Assessing the translational relevance of specific molecular pathways in spontaneous lupus mouse models.

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by loss of self-tolerance, causing inflammation and tissue damage in multiple organs. Although animal models have advanced our understanding of SLE's molecular basis, recent regulatory changes and longstanding concerns regarding reproducibility and translatability have renewed the need to critically evaluate how these models mirror human disease. Understanding pathway-level similarities and differences between mouse models and human disease is essential, given the marked clinical and molecular heterogeneity of SLE. Methods: Four spontaneous SLE mouse models were studied: MRL Results: The study identified specific molecular pathways driving the phenotype in each mouse model and established a framework describing the dynamics of these phenotype-associated molecular signatures, thereby facilitating the selection of time points of interest for future mouse-oriented experimental designs. In addition, by comparing these pathways with those observed in human SLE, we identified the most similar ones and their relationship with disease activity, providing crucial insight into their translational relevance. Importantly, disease severity across models was linked to both the extent and timing of molecular dysregulations. As expected, MRL Conclusions: These findings provide a valuable framework for future SLE research and reinforce the utility of mouse models for studying specific molecular pathways related to human SLE pathogenesis and heterogeneity. The integration of longitudinal mouse and human molecular information highlights the models that best recapitulate key aspects of human disease, offering guidance for the study of specific immunopathological mechanisms or therapeutic targets.