Triptolide ameliorates renal injury in lupus nephritis by regulating TRAF6 mRNA stability via the hsa_circ_0001439/ELAVL1 axis.

Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), is closely associated with aberrant immune-inflammatory responses. Currently, reliable non-invasive biomarkers are lacking, and existing treatments remain limited. Targeting autoimmune and inflammatory pathways offers new therapeutic potential. Triptolide (TP), a diterpenoid triepoxide compound extracted from the traditional Chinese medicine Tripterygium wilfordii, exhibits potent immunosuppressive, anti-inflammatory, and anti-proteinuric effects, demonstrating remarkable efficacy in tumors, inflammation, autoimmune diseases, and kidney-related disorders. This study investigates the mechanism by which TP ameliorates LN through the hsa_circ_0001439/ELAVL1 axis to regulate TNF receptor-associated factor 6 (TRAF6) mRNA stability. In vitro (human renal tubular epithelial cell line) and in vivo (MRL/lpr mouse model) experiments were conducted. Renal function was assessed by measuring 24-hour urinary albumin, blood urea nitrogen, and serum creatinine levels. Serum levels of inflammatory cytokines, including tumor necrosis factor-alpha, interferon-gamma, and interleukin-2, were detected by ELISA. Renal histopathological changes were observed via hematoxylin-eosin and periodic acid-Schiff staining. The cytotoxicity of TP was determined using the cell counting kit-8 (CCK-8) assay. The expression of hsa_circ_0001439, ELAVL1, and TRAF6 mRNA was measured by quantitative real-time polymerase chain reaction. Protein expression of TRAF6 and its downstream pathway components (phosphorylated p65/p65, phosphorylated p38/p38) was detected by Western blot. Apoptosis was analyzed by flow cytometry, and intracellular reactive oxygen species levels were measured to assess oxidative damage. Immunoglobulin G and complement component 3 deposition were evaluated by immunofluorescence. The interactions among hsa_circ_0001439, ELAVL1, and TRAF6 were investigated using RNA pull-down, fluorescence in situ hybridization-immunofluorescence, RNA immunoprecipitation, and dual-luciferase reporter assays. TRAF6 mRNA stability was examined following Actinomycin D treatment. Bioinformatics analysis revealed upregulation of hsa_circ_0001439 in LN (P<0.05). TP improved renal function and histopathology in LN mice (P<0.05). Silencing hsa_circ_0001439 or ELAVL1 alleviated renal injury (P<0.05), while their overexpression reversed TP's therapeutic effects (P<0.05). Hsa_circ_0001439 bound to ELAVL1 to stabilize TRAF6 mRNA (P<0.05). In rescue experiments, TP reduced inflammation (P<0.05), but hsa_circ_0001439/ELAVL1 overexpression counteracted this effect (P<0.05). TRAF6 inhibition further mitigated oxidative damage (P<0.05), confirming TRAF6 as a key target. This study elucidates that TP alleviates LN by inhibiting TRAF6-driven inflammation via the hsa_circ_0001439/ELAVL1 axis, providing a potential therapeutic target for LN treatment.