Britney Sison, Colleen M. Farley, John Wilson, Santhanam Lakshminarayanan, D. C. Roopenian, Chih‐Hao Chang
Despite recent approvals of belimumab and anifrolumab, durable, steroid-sparing remission in systemic lupus erythematosus (SLE) remains uncommon, underscoring ongoing therapeutic needs. The BXSB.Yaa mouse model, harbouring Y-linked Tlr7 duplication on a polygenic susceptibility background, has been instrumental in elucidating the TLR7-type I interferon (IFN1) axis central to SLE. This review positions BXSB.Yaa as a comparative model system and advances a mechanism-aligned framework that maps murine models to human SLE endotypes (e.g., IFN1-high vs. IFN-γ-dominant; germinal center- vs. extrafollicular-biased B-cell responses) and links those endotypes to targeted interventions. We highlight the fidelity of BXSB.Yaa to IFN1-high patient biology, and its contributions of polygenic susceptibility in driving immune cell dysregulation, cytokine imbalance, and therapeutic responsiveness to BAFF and IFN1 blockade. Notably, this model also recapitulates pathogenic pDC activation, highlighting its relevance for emerging pDC-targeted strategies. By contrasting BXSB.Yaa with other prominent lupus-prone strains (e.g., MRL/lpr, NZBWF1, NZM2410, B6.SLE1/2/3, BXD2, and Kika), we benchmark its predictive value for clinical heterogeneity and treatment response. We synthesise insights from BXSB.Yaa studies, including those that informed FDA-approved biologics, and discuss implications for next-generation precision therapies. Collectively, we advocate for BXSB.Yaa as an essential pre-clinical platform among complementary models to accelerate mechanism-based drug development and enable stratified translation in SLE research.