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The antimalarial drug hydroxychloroquine constitutes the cornerstone of standard of care for systemic lupus erythematosus, together with glucocorticoids and immunosuppressants or biologics, and all accompanied by various side effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach and Objective<\/jats:title><jats:p>Our study aimed to investigate the potential of GNS561 (ezurpimtrostat) treatment, a small basic lipophilic molecule that induces lysosomal dysregulation, using the pristane\u2010induced lupus mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Compared with hydroxychloroquine, GNS561 treatment presents a more pronounced impact on the development of pathogenic anti\u2010antibodies in pristane\u2010induced lupus mice. Next, focussing on clinical impact, we showed that GNS561 significantly reduced clinical signs of lupus in pristane\u2010induced lupus by preventing the incidence and severity of arthritis, occurrence of nephritis and lung damage. Finally, GNS561 modulated the inflammatory profile in pristane\u2010induced lupus mice through a reduction of the lipogranuloma score. Interestingly, focussing on interferon\u2010<jats:italic>\u03b1<\/jats:italic>, only pristane\u2010induced lupus mice treated by GNS561 presented a significant decrease of the cytokine, suggesting a higher efficacy for GNS561 in the modulation of lupus\u2010induced inflammation compared with hydroxychloroquine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>All results show that GNS561, but not hydroxychloroquine, represents as an effective treatment to prevent clinical and inflammatory signs of lupus in this mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Implications<\/jats:title><jats:p>Altogether, this study highlights GNS561 as a promising investigational drug for systemic lupus 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