IgA nephropathy (IgAN) remains a major cause of renal failure and mortality, and available treatments are still limited. Gui-qi-yi-shen (GQYS) granules—an established traditional Chinese medicinal formula—have long been used for IgAN, yet the molecular basis of their therapeutic effects is not fully defined. This study aimed to clarify how GQYS mediates its beneficial actions in IgAN. Eight-week-old Itgam-IRES-hCD89 mice were assigned to four experimental groups: IgAN, low-dose GQYS (GQYS-L, 5.2 g/kg), high-dose GQYS (GQYS-H, 10.4 g/kg), and Losartan (6.5 mg/kg). Age-matched C57/BL6 mice served as the control group. Therapeutic outcomes were assessed using periodic acid–Schiff (PAS) staining, serum and urine biochemical tests, and immunofluorescence (IF). To uncover mechanistic pathways, network pharmacology combined with transcriptomics was performed, followed by Western blotting and IF verification.
Relative to the IgAN model mice, both 24-hour proteinuria and alanine aminotransferase were significantly decreased in the GQYS-treated groups. PAS staining showed that mesangial cell proliferation and matrix accumulation—prominent features in IgAN—were less pronounced after GQYS intervention. IF analysis indicated reduced IgA and C3 deposition in the mesangial regions in comparison with untreated IgAN mice. Mechanistic prediction using network pharmacology and transcriptomics highlighted multiple genes and pathways potentially responsible for the actions of GQYS. Western blotting and IF confirmed that GQYS suppressed activation of the TLR4/MyD88/NF-κB and IL-6/JAK2/STAT3 signaling cascades. GQYS alleviates proteinuria and mitigates renal injury in IgAN, likely through modulation of TLR4/MyD88/NF-κB and IL-6/JAK2/STAT3 pathways, suggesting its promise as a therapeutic option.
