Redefining Preclinical Models in Systemic Lupus Erythematosus: Integrating Emerging Pathogenic Pathways and Therapeutic Directions

Preclinical animal models have served as the cornerstone of systemic lupus erythematosus (SLE) research for decades, illuminating core mechanisms of autoimmunity and end-organ damage. However, many classical murine models were established over a decade ago and do not fully reflect human disease heterogeneity or the recent breakthroughs in lupus genetics and immunology. Recent mechanistic discoveries, particularly the driving role of Toll-like receptor 7 (TLR7) gain-of-function and gene-dosage pathways in human and murine lupus pathogenesis, as well as the increasing usage of humanized mice, underscore the necessity to update how translational models are selected and evaluated. In addition, emerging intersections among immunometabolism, mitochondrial dysfunction, and gut microbiome dysbiosis require updated model systems that faithfully reproduce human immunopathology.Redefining preclinical models to incorporate these contemporary genetic and molecular drivers is essential to bridge translational gaps and guide meaningful therapeutic discovery.The primary goal of this Research Topic is to establish an updated scientific foundation that redefines preclinical models in systemic lupus erythematosus. By integrating contemporary insights from genetics, immunometabolism, and environmental interactions, this collection aims to evaluate how existing and newly engineered model systems reflect specific human SLE subsets and disease phenotypes. We seek to highlight the advantages and limitations of classical genetic strains, humanized mice, inducible models, and gene-edited platforms in modeling key pathogenic drivers such as the TLR7 pathway, nucleic acid sensing, and organ-specific damage.Furthermore, this collection will address evolving directions in preclinical drug testing, focusing on how refined model selection can better predict the efficacy of targeted biologics, small-molecule inhibitors, metabolic modulators, and cellular therapies in clinical settings. Ultimately, this topic will provide the lupus community with practical benchmarks and strategic roadmaps for preclinical translational studies.This Research Topic welcomes Original Research, Review, Mini-Review, Method, Perspective, and Opinion articles addressing the design, characterization, and translational application of preclinical SLE models. Contributions should critically evaluate how preclinical systems reflect human lupus pathogenesis and guide targeted therapeutic evaluation. We encourage studies that connect basic mechanistic immunology with translational drug discovery pipelines, including comparative assessments across different model strains and validated biomarker endpoints.Authors are also invited to discuss standardisation of preclinical protocols, therapeutic response criteria, and strategies to improve the cross-species translation of candidate therapies. Manuscripts focusing solely on descriptive phenotypic observations without mechanistic insights or clear translational relevance to SLE fall outside the primary scope of this collection.Topics include, but not limited to: • Genetic and mechanistic validation of TLR7/TLR8, nucleic acid sensing, and type I interferon pathways in murine lupus models.• The effectiveness and limitations of induced models of lupus.• Development and characterization of humanized, transgenic, and CRISPR-engineered mouse models of lupus.• Preclinical evaluation of targeted therapeutics, including small-molecule inhibitors, kinase modulators, and biological therapies.• Impact of immunometabolic alterations, mitochondrial dysfunction, and oxidative stress in preclinical disease models.• Role of gut microbiota dysbiosis and host-microbiome interactions in disease progression and model variability.• Preclinical models of lupus nephritis, neuropsychiatric lupus, and cardiovascular complications.• Study design, reproducibility standards, and clinically translatable biomarker end-points in lupus drug evaluation. Topic editors: Laurence Morel, Carla Marie Cuda, Jason Weinstein, Ziaur S. M. Rahman Source: https://www.frontiersin.org/research-topics/86189/redefining-preclinical-models-in-systemic-lupus-erythematosus-integrating-emerging-pathogenic-pathways-and-therapeutic-directions