A severely affected MRL/Lpr mouse exhibits a divergent clinical–immune profile associated with a profound metabolic alteration

Abstract Systemic lupus erythematosus (SLE) displays marked clinical and biological heterogeneity that is incompletely captured by group-based analyses. Although the MRL/Lpr mouse is a well-established lupus model, individual-level divergence within this genetically homogeneous strain remains poorly characterized. Here, we describe an MRL/Lpr mouse exhibiting an exceptionally severe systemic phenotype and provide an integrative characterization combining clinical assessment, inflammatory profiling, neuroaxonal injury, and targeted metabolomics. Despite pronounced clinical deterioration, including severe proteinuria, reduced organ weights, and marked neuroaxonal damage, this mouse did not show a globally exacerbated cytokine profile relative to other MRL/Lpr animals. In contrast, plasma neurofilament light chain levels were massively elevated, indicating substantial neuroaxonal injury. Targeted metabolomic analysis revealed a profoundly altered biochemical signature, with coordinated disruptions in nitrogen handling, sulfur amino acid metabolism, and neurometabolic pathways, clearly separating this animal from both control and lupus-prone peers. These findings illustrate that extreme disease severity can emerge independently of overt cytokine escalation and identify metabolic dysregulation as a major dimension of pathological divergence at advanced disease stages. Although descriptive and based on a single individual, this work highlights the value of extreme phenotypes for uncovering biological inflection points that remain concealed in averaged analyses and supports the integration of metabolic readouts alongside inflammatory markers in autoimmune disease research.