Dioscin attenuates Gd-IgA1 overproduction by inhibiting the IL-6-JAK2/STAT3 signaling axis in IgA nephropathy.

BACKGROUND

Inflammation is a key driver in IgA nephropathy (IgAN) pathogenesis. Recent studies have demonstrated a significant association between pro-inflammatory cytokine–triggered inflammatory cascades, particularly those involving interleukin-6 (IL-6), and disease progression in IgAN. However, the underlying molecular mechanisms remain to be fully elucidated. Dioscin (DIO), a major active compound in Yiqi Qingjie Formula— a standardized formula for IgAN treatment at Guang’anmen Hospital—has shown well-defined anti-inflammatory and immunomodulatory properties.

METHODS

Peripheral blood mononuclear cells (PBMCs) were isolated from 68 patients with IgA nephropathy (IgAN) and 16 healthy controls to assess key components of the IL-6 signaling pathway. An IgAN mouse model was established to evaluate the therapeutic effects of dioscin (DIO) and its potential anti-inflammatory mechanisms. The findings were further validated through complementary in vitro experiments.

RESULTS

We observed aberrant activation of the IL-6-mediated STAT3 signaling pathway in patients with IgAN. In vitro experiments further confirmed that IL-6 promoted the secretion of galactose-deficient IgA1 (Gd-IgA1) by activating the JAK2/STAT3 axis, which downregulated the expression of the key glycosyltransferases Core 1 β1,3-galactosyltransferase (C1GalT1) and Core 1 β3GalT-specific molecular chaperone (Cosmc). Importantly, DIO significantly inhibited JAK2/STAT3 phosphorylation in IgAN model mice, a finding that was validated again in vitro.

CONCLUSION

This study shows that DIO reduces Gd-IgA1 production and alleviates renal injury by targeting and suppressing the IL-6-JAK2/STAT3 signaling pathway, offering a promising therapeutic strategy for IgAN.