Systemic lupus erythematosus (SLE), an autoimmune disease, is characterized by the immune system targeting and damaging healthy cells and tissues across the entire body (Fortuna and Brennan, 2013). The clinical course of SLE is characterized by recurrent episodes. The primary clinical treatments include the use of steroids, immunosuppressants, antimalarial drugs, biologics, and non-steroidal anti-inflammatory drugs, among other modalities (Lazar and Kahlenberg, 2023). However, there is currently no cure for SLE, and prolonged use of medication may result in significant physical harm, including organ failure. Therefore, it is urgent to further study the pathological mechanism of SLE and explore new treatment methods.

Currently, it is widely believed that the occurrence of systemic lupus erythematosus is influenced by the interaction of multiple factors such as genetics, environment, and immunity (Bakshi et al., 2018, Goulielmos et al., 2018). The characteristics of SLE include chronic inflammation and the production of a variety of autoantibodies targeting self-antigens (Ma et al., 2019). Due to the pro-inflammatory role of macrophages in autoimmunity, they may serve as therapeutic targets for SLE (Ding et al., 2023). Macrophages are highly plastic cells with two polarized phenotypes, including classically activated macrophages (M1) and selectively activated macrophages (M2). The disruption of the delicate balance between M1/M2 phenotypes is associated with the pathogenesis of SLE (Ding et al., 2019). A study in lupus MRL/lpr mice has shown that sustained M1 infiltration in the kidneys is the cause of severe tissue damage (Iwata et al., 2012). A recent investigation has revealed that extracellular vesicles derived from bone marrow-derived mesenchymal stem cells ameliorate SLE in mice by enhancing high phagocytic activity and promoting the anti-inflammatory polarization of macrophages (Zhang et al., 2022).

Glucocorticoids are a primary pharmacological intervention for SLE (Ruiz-Irastorza, 2021). High-dose oral glucocorticoids, typically administered at a dosage of 1 mg/kg/day prednisone (PDN), have become the standard approach for managing moderate-to-severe lupus activity. Nonetheless, numerous studies have demonstrated that glucocorticoids are the primary instigator of SLE toxicity (Ruiz-Irastorza et al., 2020, Kallas et al., 2022, Durcan et al., 2016). Consequently, there is an urgent need for alternative treatment modalities that can swiftly and effectively control lupus activity, while mitigating the numerous adverse effects associated with glucocorticoid therapy.

Dihydroartemisinin (DHA), a derivative of artemisinin, has been extensively studied for its ability to modulate T lymphocyte activation and function (Li et al., 2006, Yan et al., 2019, Zhang et al., 2020). Notably, DHA has shown promising efficacy in treating autoimmune diseases such as SLE (Huang et al., 2014). Mechanistically, Li et al. demonstrated that DHA alleviates SLE symptoms by modulating the Nrf2/HO-1 pathway, which mitigates bone marrow mesenchymal stem cell senescence, a key factor in SLE pathogenesis (Li et al., 2019). Similarly, Huang et al. reported that DHA inhibits the TLR4/IRF/IFN pathway in splenocytes of MRL/lpr mice, thereby repressing LPS-induced cell activation (Huang et al., 2014). Additionally, DHA improved lupus symptoms in BXSB mice by blocking the NF-κB signaling pathway, which effectively inhibited TNF-α production (Li et al., 2006). These findings highlight the potential of DHA as a therapeutic agent for autoimmune diseases, particularly SLE. The intricate and multifaceted mechanisms inherent in traditional Chinese medicine engage a network of pathways, targets, and links. The specific influence of DHA on lupus nephritis in SLE through modulation of the M1/M2 balance remains an area of uncertainty. Moreover, the potential synergistic effects of PDN and DHA in enhancing therapeutic outcomes warrant further investigation.

Therefore, this study will clarify the role and specific molecular mechanism of PDN in combination with DHA in the progress of SLE at the cellular and animal levels, and establish a theoretical foundation for in-depth understanding of the regulatory network in the progress of SLE and the advancement of targeted drug development for anti-inflammatory purposes.