[Assessment of therapeutic effectiveness and underlying pharmacological mechanisms of Tripterygium glycosides for systemic lupus erythematosus: umbrella review and in silico study].

Abstract

Systemic lupus erythematosus(SLE) is a chronic multi-organ autoimmune disorder. Tripterygium wilfordii, a medicinal herb, possesses immunomodulatory and anti-inflammatory properties. Tripterygium glycosides(TG), as the active ingredients, are widely used in the treatment of autoimmune diseases such as SLE and rheumatoid arthritis(RA) due to their definite efficacy and are prepared into tablets for easy administration. Following the PRISMA and PRIO-Harm guidelines, this study employs a prospective registration protocol(CRD420251023354), umbrella review, and network pharmacology, molecular docking, and molecular dynamics simulation to systematically evaluate the efficacy, safety, and potential molecular mechanism of TG in the treatment of SLE. Eight databases were systematically searched. Four Meta-analyses evaluating TG combined with chemotherapy in the treatment of SLE were obtained, and their methodological quality(AMSTAR2), risk of bias(ROBIS-2), and evidence certainty(GRADE) were evaluated. At the same time, network pharmacology was employed to predict the mechanism of TG and evaluate the binding of active ingredients to targets. The results of umbrella review showed that TG significantly ameliorated SLE in terms of the renal function, immune indexes, blood parameters, and disease activity, reduced adverse reactions such as nausea, vomiting, and rash, increased the risk of irregular menstruation, and caused no significant difference in other infection risks. The methodological quality assessment found that the four systematic reviews had serious deficiencies(75% of the non-pre-registered programs and 50% of the non-exclusion lists). ROBIS-2 confirmed that all studies had a high risk of bias. GRADE classification showed that 50% of the evidence had moderate or low quality. Network pharmacology identified potential targets of TG, such as TNF and TP53, which were involved in PD-L1 expression and PD-1 checkpoint pathway in cancer and other signaling pathways. Molecular docking and kinetic simulation showed that TG might play a role by stabilizing the binding of triptoditerpenic acid B to EGFR and HIF1A. In summary, TG can significantly improve multi-system indicators of SLE but has a risk of inducing irregular menstruation. The evidence of the efficacy is limited due to methodological defects, while molecular mechanism studies have shown that TG exerts pharmacological effects through multi-target regulation of immune and metabolic pathways.