Abstract: While traditional glucocorticoids are effective in treating systemic lupusthematosus (SLE), their long-term use is associated with severe side effects. This study aims to explore the therapeutic effects of the novel dissociative steroid Vamorolone on SLE and elucidate its key immunomodulatory mechanisms. For the first time, we systematically evaluated efficacy of Vamorolone in two classical SLE animal models, providing critical preclinical evidence for its potential as an alternative to conventional glucocorticoids. In both the spontaneous lupus MRL/lpr and Pristane-induced SLE mice models, Vamorolone significantly improved survival rates, reduced serum anti-dsDNA antibody levels, and effectively ameliorated renal function indicators such as proteinuria and serum creatinine. Renal histopathological analysis revealed that Vamorolone significantly alleviated glomerular cell proliferation, basement membrane thickening, and IgG immune deposition. Mechanistically, Vamorolone exerted its effects by reshaping immune balance: it primarily increased the levels of immunosuppressive Treg cells in the MRL/lpr model, while predominantly reducing the proportion of pro-inflammatory Th17 cells in the Pristane model, achieving an effective reduction in the Th17/Treg ratio. This study confirms the significant efficacy of Vamorolone in treating SLE, demonstrating that by modulating the Th17/Treg cell balance, it effectively mitigates renal damage in SLE mice with differing pathological backgrounds. This suggests Vamorolone holds promise as a new generation of safe and effective SLE therapeutics.