Type 1 interferon (IFN-1) signaling is implicated in the pathogenesis of lupus nephritis (LN). Systemic lupus erythematosus (SLE) patients with elevated IFN-1 expression are more susceptible to developing LN. Our preliminary findings indicated that the gene expression profile induced by Proscillaridin A (PSD-A) exhibited an inverse correlation with the molecular signatures associated with LN, potentially through the inhibition of the IFN-1 signaling pathway. This research aims to investigate the protective effects of PSD-A on podocyte injury in LN and the underlying mechanisms involved.

Molecular docking and surface plasmon resonance techniques were employed to analyze the binding between PSD-A and signal transducer and activator of transcription 1 (STAT1). Human podocytes injury model induced by serum from LN patients was established, with blank control and PSD-A treatment groups. Western blot and quantitative real-time PCR were utilized to assess the relative protein and mRNA expression levels of podocin, STAT1, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) in podocytes across different groups. C57BL/6 mice served as the control group, while MRL/lpr lupus mice were randomly divided into lupus and treatment groups using a random number table. The treatment group received intraperitoneal injections of 5 mg/kg PSD-A, whereas the control and lupus groups were administered an equivalent volume of solvent without PSD-A. Serum levels of anti-dsDNA antibodies and interferon-α (IFN-α) were measured by ELISA. Urinary protein levels were determined using the Coomassie Brilliant Blue (CBB) method. Renal histopathological changes were examined by light microscopy, and the expression of podocin, STAT1, and IFIT1 in renal podocytes was evaluated via immunohistochemistry.

Molecular docking analyses and surface plasmon resonance assays confirmed a strong binding affinity between PSD-A and the STAT1 protein. In experiments involving podocytes treated with serum from LN patients, results indicated that, compared to the lupus group, the PSD-A intervention group exhibited upregulation of podocin protein and mRNA expression, along with downregulation of STAT1 and IFIT1 protein and mRNA expression (all P<0.05), demonstrating a dose-dependent effect. Compared with MRL/lpr lupus mice, the PSD-A treatment group exhibited reduced serum levels of anti-dsDNA antibodies and IFN-α, decreased urinary protein excretion, and alleviated pathological damage in renal tissues, along with attenuated podocyte injury. Immunohistochemical staining of renal tissues revealed that the relative expression levels of STAT1 and IFIT1 were significantly lower in the PSD-A intervention group than in the lupus group (all P<0.05).

PSD-A exerts a protective effect against podocyte injury in lupus nephritis, potentially through the suppression of the STAT1 signaling pathway.