Over the past few decades, the prognosis for SLE has improved substantially due to the use of glucocorticoids, immunosuppressants, and biologics. As a result, the survival rate among SLE patients has significantly increased, with reports indicating a 10-year survival rate of over 90%.13 However, the standardized mortality rate for SLE remains 2 to 3 times higher than that of the general population, a discrepancy partly attributed to adverse reactions.14 Traditional Chinese Medicine often employs Rehmannia glutinosa in the treatment of SLE, and formulas containing this ingredient have demonstrated effective outcomes with minimal side effects.15 RA is a monomeric component derived from Rehmannia glutinosa, and recent research suggests it has a potential therapeutic effect on SLE.
In this study, we constructed a gene network associated with RA against SLE, featuring 74 identified targets. Using GO and KEGG analysis, our study suggests that RA has the potential to modulate several crucial biological processes, such as oxidative stress, apoptosis, and immune response pathways. From the PPI network, we identified five core targets: HSP90AA1, HIF1A, PIK3CA, MTOR, and TLR4. These targets play a significant role in treating SLE and are involved in oxidative stress, immune regulation, and inflammation.
HSP90 is overexpressed in SLE patients and correlates with elevated IL-6 levels. Additionally, autoantibodies against HSP90 can be detected in SLE patients.16 In MRL/lpr mice, HSP90 regulates T cell differentiation and activation, and its inhibition can mitigate SLE inflammation.17 Furthermore, Single Nucleotide Polymorphisms of the HSP90AA1 gene may influence the responsiveness of SLE patients to glucocorticoids.18
HIF-1 can activate RORγt, which forms a tertiary complex with p300 and the IL-17 promoter, thus regulating Th17 signature genes and promoting Th17 development. Concurrently, HIF-1 can suppress the development of Treg cells by binding to the transcription factor Foxp3.19,20
mTOR is pivotal in chronic inflammation. A retrospective study indicated that mTOR inhibitors could potentially be safe and effective for treating grade III/IV/V lupus nephritis.21 These inhibitors can suppress B cell production of autoantibodies and reverse Treg cell depletion in SLE.22,23 Moreover, mTOR inhibitors can restrict B cell proliferation induced by BAFF and limit pDCs’ production of IFN-α.24,25
TLR4 is associated with autoantibody production and glomerulonephritis in SLE. TLR4-deficient C57BL/6lpr/lpr mice exhibited reduced kidney damage and lower titers of anti-nuclear, anti-dsDNA, and anticardiolipin antibodies compared to TLR4-producing counterparts.26 Blocking TLR4 signaling can notably inhibit autoantibody secretion by SLE patient plasma cells.27
A total of 715 biological functions and 128 signaling pathways were enriched by GO and KEGG analysis, suggesting that the biological functions and signaling pathways of these targets may be the mechanism of RA in the treatment of SLE. More and more studies have reported that PI3K/ Akt signaling pathway is involved in the pathogenesis of SLE. The PI3K/Akt/mTOR pathway is generally activated in SLE patients. The activation of the pathway increases the levels of IL-17 and IL-4 which inhibits Treg cells and promotes the abnormal activation of T cells.28, 29 Inhibition of the p110γ subunit of PI3K in MRL-lpr mice can effectively alleviate glomerulonephritis, and reduce the number of autoantibodies and pathological CD4 + T cells.30 In addition, the Akt/mTOR pathway was found to be activated in B cells in lupus mice, and the degree of activation paralleled the disease severity.31 Belimumab is a monoclonal antibody against BAFF, which has definite efficacy in SLE. BAFF is a promoter of mTOR activation, and the use of mTOR inhibitors can block the activation of mTOR stimulated by BAFF, reduce proliferation of B cells and induce apoptosis of B cells.32 The activation of PI3K/ Akt signaling pathway can also lead to the release of a large number of Neutrophil Extracellular Traps (NETs) from neutrophils.33 NETs as autoantigens can induce the production of anti-NET antibodies, which can trigger or aggravate SLE34. The above results were consistent with the results of GO and KEGG analysis in this study.
Molecular docking results showed that RA had strong docking activity with the core targets. The molecular mechanisms of RA against SLE were verified by molecular docking and molecular dynamics simulation. Molecular docking analysis revealed that RA had different affinities with the screened key protein targets, among which MTOR had the highest affinity. Molecular dynamics simulation showed that RA was stable when combined with MTOR, implying that MTOR is a key link in the ability of RA to resist SLE.
In the present study, we utilized a comprehensive analytical approach—integrating network pharmacology, molecular docking, and molecular dynamics simulations—to uncover the potential mechanism through which RA combats SLE. Although our study provides novel insights, it has limitations, primarily the need for further experimental validation to corroborate our findings. Nevertheless, our work establishes a foundation for future research, offering both a direction for investigation and theoretical underpinnings to guide further exploration in this field.