Evaluating the efficacy of SK1217 in attenuating pristane-induced lupus in mice

Introduction Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder characterized by aberrant immune activation, autoantibody production, immune complex deposition, and progressive organ damage, particularly lupus nephritis. Developing therapies that can simultaneously modulate immune dysregulation and inflammation remains a major clinical need. Methods In the present study, we evaluated the therapeutic efficacy of the antimicrobial and immunomodulatory peptide SK1217 in a pristane-induced lupus mouse model. Disease progression and therapeutic effects were assessed through measurement of serum autoantibodies, proinflammatory cytokines, complement levels, renal function markers, and immune cell populations. Molecular mechanisms were investigated by analyzing MAPK and NF-κB signaling pathways in renal tissues. Results SK1217 treatment significantly reduced serum autoantibody levels, including anti-dsDNA, anti-ssDNA, anti-chromatin, anti-ANA, and anti-nRNP antibodies. The peptide also suppressed proinflammatory cytokines TNF-α, IL-1β, IL-6, and IL-17. Mechanistically, SK1217 attenuated activation of inflammatory signaling pathways, as demonstrated by reduced phosphorylation of JNK and p38 MAPK and downregulation of NF-κB p65. SK1217 further modulated humoral immune responses by decreasing serum BAFF levels and altering splenic CD40 + activated B cells and CD138 + plasma cell populations, accompanied by reduced total serum IgG levels. Complement balance was restored through normalization of serum C3 levels. Functionally, SK1217 improved renal parameters by reducing urinary protein excretion, serum creatinine, and blood urea nitrogen levels, and ameliorated glomerular pathology. Additionally, the peptide modulated immune cell dynamics by reducing Ly6C hi monocytes and regulating peritoneal macrophage and granulocyte populations. Discussion Collectively, these findings demonstrate that SK1217 exerts multi-target immunomodulatory and renoprotective effects through coordinated suppression of BAFF-driven B cell activation, inflammatory cytokine production, complement activation, and MAPK/NF-κB signaling pathways. These results highlight SK1217 as a promising therapeutic candidate for SLE and lupus nephritis, warranting further translational investigation.