Abstract: Objective To explore the therapeutic mechanism of Jianpi Zishen (JPZS) granules for systemic lupus erythematosus (SLE) in light of podocyte autophagy regulation. Methods TCMSP, GeneCards, OMIM, and TTD databases were used to obtain the targets of JPZS granules, SLE, and podocyte autophagy. The protein-protein interaction network was constructed using Cytoscape, and the key active ingredients and targets were screened for molecular docking. In the clinical study, 46 patients with SLE were randomized into two groups to receive baseline treatment with prednisone acetate and mycophenolate mofetil (control group) and additional treatment with JPZS granules (observation group) for 12 weeks, with 10 healthy volunteers as the healthy control group. Urinary levels of nephrin and synaptopodin of the patients were detected with ELISA. Western blotting was performed to determine peripheral blood levels of p- JAK1/JAK1, p-STAT1/STAT1, LC3II/LC3I, and p62 proteins of the participants. Results Four key active ingredients and 5 core target genes (STAT1, PIK3CG, MAPK1, PRKCA, and CJA1) were obtained, and enrichment analysis identified the potentially involved signaling pathways including AGE-RAGE, JAK/STAT, EGFR, and PI3K/Akt. Molecular docking analysis showed that STAT1 was the most promising target protein with the highest binding activity, suggesting its role as an important mediator for signal transduction after JPZS granule treatment. In the 43 SLE patients available for analysis, treatment with JPZS granule significantly reduced serum levels of p- JAK1/JAK1, p- STAT1/STAT1, and LC3II/LC3I (P<0.05 or 0.01), increased the protein level of P62 (P<0.05), and reduced urinary levels of nephrin and synaptopodin (P<0.05). Conclusion The therapeutic effect of JPZS granules on SLE is mediated probably by coordinated actions of quercetin, kaempferol, β-sitosterol, and isorhamnetin on their target gene STAT1 to inhibit the JAK/STAT pathway, thus suppressing autophagy and alleviating podocyte injuries in SLE.

Key words: systemic lupus erythematosus; Jianpi Zishen granules; network pharmacology; podocytes; autophagy